Heat shock protein inhibitors: success stories
- McAlpine, Shelli R, Edkins, Adrienne L
- Authors: McAlpine, Shelli R , Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/66359 , vital:28940 , https://doi.org/10.1007/978-3-319-32607-8
- Description: publisher version , Introduction: Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors. , This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98566), the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA) and Rhodes University. The views expressed are those of the authors and should not be attributed to the DST, NRF, CANSA, MRC-SA or Rhodes University. We apologize if we have inadvertently missed any important contributions to the field.
- Full Text: false
- Date Issued: 2016
- Authors: McAlpine, Shelli R , Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/66359 , vital:28940 , https://doi.org/10.1007/978-3-319-32607-8
- Description: publisher version , Introduction: Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors. , This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98566), the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA) and Rhodes University. The views expressed are those of the authors and should not be attributed to the DST, NRF, CANSA, MRC-SA or Rhodes University. We apologize if we have inadvertently missed any important contributions to the field.
- Full Text: false
- Date Issued: 2016
Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective
- Edkins, Adrienne L, Price, John T, Pockley, A Graham, Blatch, Gregory L
- Authors: Edkins, Adrienne L , Price, John T , Pockley, A Graham , Blatch, Gregory L
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164332 , vital:41109 , DOI: 10.1098/rstb.2016.0521
- Description: Many heat shock proteins (HSPs) are essential to survival as a consequence of their role as molecular chaperones, and play a critical role in maintaining cellular proteostasis by integrating the fundamental processes of protein folding and degradation. HSPs are arguably among the most prominent classes of proteins that have been broadly linked to many human disorders, with changes in their expression profile and/or intracellular/extracellular location now being described as contributing to the pathogenesis of a number of different diseases. Although the concept was initially controversial, it is now widely accepted that HSPs have additional biological functions over and above their role in proteostasis (so-called ‘protein moonlighting’).
- Full Text:
- Date Issued: 2017
- Authors: Edkins, Adrienne L , Price, John T , Pockley, A Graham , Blatch, Gregory L
- Date: 2017
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164332 , vital:41109 , DOI: 10.1098/rstb.2016.0521
- Description: Many heat shock proteins (HSPs) are essential to survival as a consequence of their role as molecular chaperones, and play a critical role in maintaining cellular proteostasis by integrating the fundamental processes of protein folding and degradation. HSPs are arguably among the most prominent classes of proteins that have been broadly linked to many human disorders, with changes in their expression profile and/or intracellular/extracellular location now being described as contributing to the pathogenesis of a number of different diseases. Although the concept was initially controversial, it is now widely accepted that HSPs have additional biological functions over and above their role in proteostasis (so-called ‘protein moonlighting’).
- Full Text:
- Date Issued: 2017
Heterodimer formation by Oct4 and Smad3 differentially regulates epithelial-to-mesenchymal transition-associated factors in breast cancer progression:
- Mandal, Gunjan, Biswas, Subir, Chowdhury, Sougata R, Chatterjee, Annesha, Purohit, Suman, Khamaru, Poulomi, Chakraborty, Sayan, Mandal, Palash K, Gupta, Arnab, de la Mare, Jo-Anne, Edkins, Adrienne L, Bhattacharyya, Arindam
- Authors: Mandal, Gunjan , Biswas, Subir , Chowdhury, Sougata R , Chatterjee, Annesha , Purohit, Suman , Khamaru, Poulomi , Chakraborty, Sayan , Mandal, Palash K , Gupta, Arnab , de la Mare, Jo-Anne , Edkins, Adrienne L , Bhattacharyya, Arindam
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164907 , vital:41183 , DOI: 10.1016/j.bbadis.2018.03.010
- Description: The multifunctional cytokine TGF-β crucially participates in breast cancer (BCa) metastasis and works differently in the disease stages, thus contributing in BCa progression. We address connections between TGF-β and the stem cell-related transcription factor (TF) Oct4 in BCa. In 147 BCa patients with infiltrating duct carcinoma, we identified a significantly higher number of cases with both moderate/high Oct4 expression and high TGF-β in late stages compared to early stages of the disease.
- Full Text:
- Date Issued: 2018
- Authors: Mandal, Gunjan , Biswas, Subir , Chowdhury, Sougata R , Chatterjee, Annesha , Purohit, Suman , Khamaru, Poulomi , Chakraborty, Sayan , Mandal, Palash K , Gupta, Arnab , de la Mare, Jo-Anne , Edkins, Adrienne L , Bhattacharyya, Arindam
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164907 , vital:41183 , DOI: 10.1016/j.bbadis.2018.03.010
- Description: The multifunctional cytokine TGF-β crucially participates in breast cancer (BCa) metastasis and works differently in the disease stages, thus contributing in BCa progression. We address connections between TGF-β and the stem cell-related transcription factor (TF) Oct4 in BCa. In 147 BCa patients with infiltrating duct carcinoma, we identified a significantly higher number of cases with both moderate/high Oct4 expression and high TGF-β in late stages compared to early stages of the disease.
- Full Text:
- Date Issued: 2018
Hop depletion reduces HSF1 levels and activity and coincides with reduced stress resilience:
- Chakraborty, Abantika, Edkins, Adrienne L
- Authors: Chakraborty, Abantika , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165440 , vital:41244 , https://doi.org/10.1016/j.bbrc.2020.04.072
- Description: Heat-shock factor 1 (HSF1) regulates the transcriptional response to stress and controls expression of molecular chaperones required for cell survival. Here we report that HSF1 is regulated by the abundance of the Hsp70-Hsp90 organizing protein (Hop/STIP1).
- Full Text:
- Date Issued: 2020
- Authors: Chakraborty, Abantika , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165440 , vital:41244 , https://doi.org/10.1016/j.bbrc.2020.04.072
- Description: Heat-shock factor 1 (HSF1) regulates the transcriptional response to stress and controls expression of molecular chaperones required for cell survival. Here we report that HSF1 is regulated by the abundance of the Hsp70-Hsp90 organizing protein (Hop/STIP1).
- Full Text:
- Date Issued: 2020
HOP expression is regulated by p53 and RAS and characteristic of a cancer gene signature
- Mattison, Stacey A, Blatch, Gregory L, Edkins, Adrienne L
- Authors: Mattison, Stacey A , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66278 , vital:28928 , https://doi.org/10.1007/s12192-016-0755-8
- Description: publisher version , The Hsp70/Hsp90 organising protein (HOP) is a co-chaperone essential for client protein transfer from Hsp70 to Hsp90 within the Hsp90 chaperone machine. Although HOP is upregulated in various cancers, there is limited information from in vitro studies on how HOP expression is regulated in cancer. The main objective of this study was to identify the HOP promoter and investigate its activity in cancerous cells. Bioinformatic analysis of the -2500 to +16 bp region of the HOP gene identified a large CpG island and a range of putative cis-elements. Many of the cis-elements were potentially bound by transcription factors which are activated by oncogenic pathways. Luciferase reporter assays demonstrated that the upstream region of the HOP gene contains an active promoter in vitro. Truncation of this region suggested that the core HOP promoter region was -855 to +16 bp. HOP promoter activity was highest in Hs578T, HEK293T and SV40- transformed MEF1 cell lines which expressed mutant or inactive p53. In a mutant p53 background, expression of wild-type p53 led to a reduction in promoter activity, while inhibition of wild-type p53 in HeLa cells increased HOP promoter activity. Additionally, in Hs578T and HEK293T cell lines containing inactive p53, expression of HRAS increased HOP promoter activity. However, HRAS activation of the HOP promoter was inhibited by p53 overexpression. These findings suggest for the first time that HOP expression in cancer may be regulated by both RAS activation and p53 inhibition. Taken together, these data suggest that HOP may be part of the cancer gene signature induced by a combination of mutant p53 and mutated RAS that is associated with cellular transformation.
- Full Text: false
- Date Issued: 2018
- Authors: Mattison, Stacey A , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66278 , vital:28928 , https://doi.org/10.1007/s12192-016-0755-8
- Description: publisher version , The Hsp70/Hsp90 organising protein (HOP) is a co-chaperone essential for client protein transfer from Hsp70 to Hsp90 within the Hsp90 chaperone machine. Although HOP is upregulated in various cancers, there is limited information from in vitro studies on how HOP expression is regulated in cancer. The main objective of this study was to identify the HOP promoter and investigate its activity in cancerous cells. Bioinformatic analysis of the -2500 to +16 bp region of the HOP gene identified a large CpG island and a range of putative cis-elements. Many of the cis-elements were potentially bound by transcription factors which are activated by oncogenic pathways. Luciferase reporter assays demonstrated that the upstream region of the HOP gene contains an active promoter in vitro. Truncation of this region suggested that the core HOP promoter region was -855 to +16 bp. HOP promoter activity was highest in Hs578T, HEK293T and SV40- transformed MEF1 cell lines which expressed mutant or inactive p53. In a mutant p53 background, expression of wild-type p53 led to a reduction in promoter activity, while inhibition of wild-type p53 in HeLa cells increased HOP promoter activity. Additionally, in Hs578T and HEK293T cell lines containing inactive p53, expression of HRAS increased HOP promoter activity. However, HRAS activation of the HOP promoter was inhibited by p53 overexpression. These findings suggest for the first time that HOP expression in cancer may be regulated by both RAS activation and p53 inhibition. Taken together, these data suggest that HOP may be part of the cancer gene signature induced by a combination of mutant p53 and mutated RAS that is associated with cellular transformation.
- Full Text: false
- Date Issued: 2018
Hop/STIP1 depletion alters nuclear structure via depletion of nuclear structural protein emerin:
- Kituyi, Sarah N, Edkins, Adrienne L
- Authors: Kituyi, Sarah N , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164435 , vital:41118 , https://doi.org/10.1016/j.bbrc.2018.11.073
- Description: Hop/STIP1 is a co-chaperone of Hsp70 and Hsp90 that regulates a number of cell biology processes via interactions with cellular proteins. Here we report a new relationship between Hop and the nuclear structural protein emerin in maintenance of nuclear morphology. Depletion or overexpression of Hop resulted in the reduction of emerin protein levels via proteasomal and lysosomal pathways.
- Full Text:
- Date Issued: 2018
- Authors: Kituyi, Sarah N , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164435 , vital:41118 , https://doi.org/10.1016/j.bbrc.2018.11.073
- Description: Hop/STIP1 is a co-chaperone of Hsp70 and Hsp90 that regulates a number of cell biology processes via interactions with cellular proteins. Here we report a new relationship between Hop and the nuclear structural protein emerin in maintenance of nuclear morphology. Depletion or overexpression of Hop resulted in the reduction of emerin protein levels via proteasomal and lysosomal pathways.
- Full Text:
- Date Issued: 2018
Hsp40 Co-chaperones as drug targets: towards the development of specific inhibitors
- Pesce, Eva-Rachele, Blatch, Gregory L, Edkins, Adrienne L
- Authors: Pesce, Eva-Rachele , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66335 , vital:28937 , https://doi.org/10.1007/7355_2015_92
- Description: publisher version , The heat shock protein 40 (Hsp40/DNAJ) family of co-chaperones modulates the activity of the major molecular chaperone heat shock protein 70 (Hsp70) protein group. Hsp40 stimulates the basal ATPase activity of Hsp70 and hence regulates the affinity of Hsp70 for substrate proteins. The number of Hsp40 genes in most organisms is substantially greater than the number of Hsp70 genes. Therefore, different Hsp40 family members may regulate different activities of the same Hsp70. This fact, along with increasing knowledge of the function of Hsp40 in diseases, has led to certain Hsp40 isoforms being considered promising drug targets. Here we review the role of Hsp40 in human disease and recent developments towards the creation of Hsp40-specific inhibitors.
- Full Text: false
- Date Issued: 2016
- Authors: Pesce, Eva-Rachele , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66335 , vital:28937 , https://doi.org/10.1007/7355_2015_92
- Description: publisher version , The heat shock protein 40 (Hsp40/DNAJ) family of co-chaperones modulates the activity of the major molecular chaperone heat shock protein 70 (Hsp70) protein group. Hsp40 stimulates the basal ATPase activity of Hsp70 and hence regulates the affinity of Hsp70 for substrate proteins. The number of Hsp40 genes in most organisms is substantially greater than the number of Hsp70 genes. Therefore, different Hsp40 family members may regulate different activities of the same Hsp70. This fact, along with increasing knowledge of the function of Hsp40 in diseases, has led to certain Hsp40 isoforms being considered promising drug targets. Here we review the role of Hsp40 in human disease and recent developments towards the creation of Hsp40-specific inhibitors.
- Full Text: false
- Date Issued: 2016
Hsp70/Hsp90 organising protein (hop): beyond interactions with chaperones and prion proteins
- Baindur-Hudson, Swati, Edkins, Adrienne L, Blatch, Gregory L
- Authors: Baindur-Hudson, Swati , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2015
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164852 , vital:41178 , ISBN 978-3-319-11730-0 , DOI: 10.1007/978-3-319-11731-7_3
- Description: The Hsp70/Hsp90 organising protein (Hop), also known as stress-inducible protein 1 (STI1), has received considerable attention for diverse cellular functions in both healthy and diseased states. There is extensive evidence that intracellular Hop is a co-chaperone of the major chaperones Hsp70 and Hsp90, playing an important role in the productive folding of Hsp90 client proteins. Consequently, Hop is implicated in a number of key signalling pathways, including aberrant pathways leading to cancer. However, Hop is also secreted and it is now well established that Hop also serves as a receptor for the prion protein, PrPC.
- Full Text:
- Date Issued: 2015
- Authors: Baindur-Hudson, Swati , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2015
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/164852 , vital:41178 , ISBN 978-3-319-11730-0 , DOI: 10.1007/978-3-319-11731-7_3
- Description: The Hsp70/Hsp90 organising protein (Hop), also known as stress-inducible protein 1 (STI1), has received considerable attention for diverse cellular functions in both healthy and diseased states. There is extensive evidence that intracellular Hop is a co-chaperone of the major chaperones Hsp70 and Hsp90, playing an important role in the productive folding of Hsp90 client proteins. Consequently, Hop is implicated in a number of key signalling pathways, including aberrant pathways leading to cancer. However, Hop is also secreted and it is now well established that Hop also serves as a receptor for the prion protein, PrPC.
- Full Text:
- Date Issued: 2015
Hsp90 binds directly to fibronectin (FN) and inhibition reduces the extracellular fibronectin matrix in breast cancer cells:
- Hunter, Morgan C, O’Hagan, Kyle L, Kenyon, Amy, Dhanani, Karim C H, Prinsloo, Earl, Edkins, Adrienne L
- Authors: Hunter, Morgan C , O’Hagan, Kyle L , Kenyon, Amy , Dhanani, Karim C H , Prinsloo, Earl , Edkins, Adrienne L
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164841 , vital:41177 , DOI: 10.1371/journal.pone.0086842
- Description: Heat shock protein 90 (Hsp90) has been identified in the extracellular space and has been shown to chaperone a finite number of extracellular proteins involved in cell migration and invasion. We used chemical cross-linking and immunoprecipitation followed by tandem mass spectrometry (MS/MS) to isolate a complex containing Hsp90 and the matrix protein fibronectin (FN) from breast cancer cells.
- Full Text:
- Date Issued: 2014
- Authors: Hunter, Morgan C , O’Hagan, Kyle L , Kenyon, Amy , Dhanani, Karim C H , Prinsloo, Earl , Edkins, Adrienne L
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164841 , vital:41177 , DOI: 10.1371/journal.pone.0086842
- Description: Heat shock protein 90 (Hsp90) has been identified in the extracellular space and has been shown to chaperone a finite number of extracellular proteins involved in cell migration and invasion. We used chemical cross-linking and immunoprecipitation followed by tandem mass spectrometry (MS/MS) to isolate a complex containing Hsp90 and the matrix protein fibronectin (FN) from breast cancer cells.
- Full Text:
- Date Issued: 2014
Hsp90 co-chaperones as drug targets in cancer: current perspectives
- Authors: Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66347 , vital:28938 , https://doi.org/10.1007/7355_2015_99
- Description: publisher version , Hsp90 is a molecular chaperone that regulates the function of numerous oncogenic transcription factors and signalling intermediates in the cell. Inhibition of Hsp90 is sufficient to induce the proteosomal degradation of many of these proteins, and as such, the Hsp90 chaperone has been regarded as a promising drug target. The appropriate functioning of the Hsp90 chaperone is dependent on its ATPase activity and interactions with a cohort of non-substrate accessory proteins known as co-chaperones. Co-chaperones associate with Hsp90 at all stages of the chaperone cycle and regulate a range of Hsp90 functions, including ATP hydrolysis and client protein binding and release. Given the ability of co-chaperones to organise the function of the Hsp90 molecular machine, these proteins are now regarded as potential drug targets. Herein the role of selected Hsp90 co-chaperones Hop, Cdc37, p23 and Aha1 as possible drug targets is discussed with a focus on cancer. , This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98566), the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA) and Rhodes University. The views expressed are those of the authors and should not be attributed to the DST, NRF, CANSA, MRC-SA or Rhodes University. We apologize if we have inadvertently missed any important contributions to the field.
- Full Text: false
- Date Issued: 2016
- Authors: Edkins, Adrienne L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66347 , vital:28938 , https://doi.org/10.1007/7355_2015_99
- Description: publisher version , Hsp90 is a molecular chaperone that regulates the function of numerous oncogenic transcription factors and signalling intermediates in the cell. Inhibition of Hsp90 is sufficient to induce the proteosomal degradation of many of these proteins, and as such, the Hsp90 chaperone has been regarded as a promising drug target. The appropriate functioning of the Hsp90 chaperone is dependent on its ATPase activity and interactions with a cohort of non-substrate accessory proteins known as co-chaperones. Co-chaperones associate with Hsp90 at all stages of the chaperone cycle and regulate a range of Hsp90 functions, including ATP hydrolysis and client protein binding and release. Given the ability of co-chaperones to organise the function of the Hsp90 molecular machine, these proteins are now regarded as potential drug targets. Herein the role of selected Hsp90 co-chaperones Hop, Cdc37, p23 and Aha1 as possible drug targets is discussed with a focus on cancer. , This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 98566), the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA) and Rhodes University. The views expressed are those of the authors and should not be attributed to the DST, NRF, CANSA, MRC-SA or Rhodes University. We apologize if we have inadvertently missed any important contributions to the field.
- Full Text: false
- Date Issued: 2016
HSP90 interacts with the fibronectin N-terminal domains and increases matrix formation:
- Chakraborty, Abir, Boel, Natasha M-E, Edkins, Adrienne L
- Authors: Chakraborty, Abir , Boel, Natasha M-E , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165407 , vital:41241 , https://doi.org/10.3390/cells9020272
- Description: Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the morphology of the extracellular matrix. Here, we further characterized the HSP90 and FN interaction. FN bound to the M domain of HSP90 and interacted with both the open and closed HSP90 conformations; and the interaction was reduced in the presence of sodium molybdate. HSP90 interacted with the N-terminal regions of FN, which are known to be important for matrix assembly.
- Full Text:
- Date Issued: 2020
- Authors: Chakraborty, Abir , Boel, Natasha M-E , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165407 , vital:41241 , https://doi.org/10.3390/cells9020272
- Description: Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the morphology of the extracellular matrix. Here, we further characterized the HSP90 and FN interaction. FN bound to the M domain of HSP90 and interacted with both the open and closed HSP90 conformations; and the interaction was reduced in the presence of sodium molybdate. HSP90 interacted with the N-terminal regions of FN, which are known to be important for matrix assembly.
- Full Text:
- Date Issued: 2020
Hsp90α/β associates with the GSK3β/axin1/phospho-β-catenin complex in the human MCF-7 epithelial breast cancer model:
- Cooper, Leanne C, Prinsloo, Earl, Edkins, Adrienne L, Blatch, Gregory L
- Authors: Cooper, Leanne C , Prinsloo, Earl , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165096 , vital:41208 , DOI: 10.1016/j.bbrc.2011.08.136
- Description: Hsp90α/β, the signal transduction chaperone, maintains intracellular communication in normal, stem, and cancer cells. The well characterised association of Hsp90α/β with its client kinases form the framework of multiple signalling networks. GSK3β, a known Hsp90α/β client, mediates β-catenin phosphorylation as part of a cytoplasmic destruction complex which targets phospho-β-catenin to the 26S proteasome. The canonical Wnt/β-catenin pathway promotes stem cell self-renewal as well as oncogenesis. The degree of Hsp90α/β involvement in Wnt/β-catenin signalling needs clarification. Here, we describe the association of Hsp90α/β with GSK3β, β-catenin, phospho-β-catenin and the molecular scaffold, axin1, in the human MCF-7 epithelial breast cancer cell model using selective inhibition of Hsp90α/β, confocal laser scanning microscopy and immunoprecipitation. Our findings suggest that Hsp90α/β modulates the phosphorylation of β-catenin by interaction in common complex with GSK3β/axin1/β-catenin.
- Full Text:
- Date Issued: 2011
- Authors: Cooper, Leanne C , Prinsloo, Earl , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165096 , vital:41208 , DOI: 10.1016/j.bbrc.2011.08.136
- Description: Hsp90α/β, the signal transduction chaperone, maintains intracellular communication in normal, stem, and cancer cells. The well characterised association of Hsp90α/β with its client kinases form the framework of multiple signalling networks. GSK3β, a known Hsp90α/β client, mediates β-catenin phosphorylation as part of a cytoplasmic destruction complex which targets phospho-β-catenin to the 26S proteasome. The canonical Wnt/β-catenin pathway promotes stem cell self-renewal as well as oncogenesis. The degree of Hsp90α/β involvement in Wnt/β-catenin signalling needs clarification. Here, we describe the association of Hsp90α/β with GSK3β, β-catenin, phospho-β-catenin and the molecular scaffold, axin1, in the human MCF-7 epithelial breast cancer cell model using selective inhibition of Hsp90α/β, confocal laser scanning microscopy and immunoprecipitation. Our findings suggest that Hsp90α/β modulates the phosphorylation of β-catenin by interaction in common complex with GSK3β/axin1/β-catenin.
- Full Text:
- Date Issued: 2011
Human DNAJ in cancer and stem cells:
- Sterrenberg, Jason N, Edkins, Adrienne L, Blatch, Gregory L
- Authors: Sterrenberg, Jason N , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165118 , vital:41210 , DOI: 10.1016/j.canlet.2011.08.019
- Description: The heat shock protein 40 kDa (HSP40/DNAJ) co-chaperones constitute the largest and most diverse sub-group of the heat shock protein (HSP) family. DNAJ are widely accepted as regulators of HSP70 function, but also have roles as co-chaperones for the HSP90 chaperone machine, and a growing number of biological functions that may be independent of either of these chaperones. The DNAJ proteins are differentially expressed in human tissues and demonstrate the capacity to function to both promote and suppress cancer development by acting as chaperones for tumour suppressors or oncoproteins. We review the current literature on the function and expression of DNAJ in cancer, stem cells and cancer stem cells. Combining data from gene expression, proteomics and studies in other systems, we propose that DNAJ will be key regulators of cancer, stem cell and possibly cancer stem cell function. The diversity of DNAJ and their assorted roles in a range of biological functions means that selected DNAJ, provided there is limited redundancy and that a specific link to malignancy can be established, may yet provide an attractive target for specific and selective drug design for the development of anti-cancer treatments.
- Full Text:
- Date Issued: 2011
- Authors: Sterrenberg, Jason N , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165118 , vital:41210 , DOI: 10.1016/j.canlet.2011.08.019
- Description: The heat shock protein 40 kDa (HSP40/DNAJ) co-chaperones constitute the largest and most diverse sub-group of the heat shock protein (HSP) family. DNAJ are widely accepted as regulators of HSP70 function, but also have roles as co-chaperones for the HSP90 chaperone machine, and a growing number of biological functions that may be independent of either of these chaperones. The DNAJ proteins are differentially expressed in human tissues and demonstrate the capacity to function to both promote and suppress cancer development by acting as chaperones for tumour suppressors or oncoproteins. We review the current literature on the function and expression of DNAJ in cancer, stem cells and cancer stem cells. Combining data from gene expression, proteomics and studies in other systems, we propose that DNAJ will be key regulators of cancer, stem cell and possibly cancer stem cell function. The diversity of DNAJ and their assorted roles in a range of biological functions means that selected DNAJ, provided there is limited redundancy and that a specific link to malignancy can be established, may yet provide an attractive target for specific and selective drug design for the development of anti-cancer treatments.
- Full Text:
- Date Issued: 2011
In vitro analysis of putative cancer stem cell populations and chemosensitivity in the SW480 and SW620 colon cancer metastasis model:
- Slater, Cindy, de la Mare, Jo-Anne, Edkins, Adrienne L
- Authors: Slater, Cindy , de la Mare, Jo-Anne , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164401 , vital:41115 , DOI: 10.3892/ol.2018.8431
- Description: The cancer stem cell (CSC) theory implicates a small subpopulation of cells with stem like properties, which is responsible for tumour initiation, development and metastasis. The unique biological and functional characteristics of CSCs, widely associated with treatment resistance, indicate an association between metastasis and stemness. It was hypothesised that metastatic cell lines may be enriched in CSCs and that this would correlate with a more resistant tumour. In the present study, the SW480 and SW620 paired cell lines derived from a colon adenocarcinoma and its lymph node metastasis, respectively were compared as an in vitro model of cancer progression. Their chemosensitivity and CSC properties were investigated. A range of in vitro assays were performed, including the side population assay, ALDEFLUOR assay, tumoursphere assay and assessment of CSC associated surface phenotypes.
- Full Text:
- Date Issued: 2018
- Authors: Slater, Cindy , de la Mare, Jo-Anne , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164401 , vital:41115 , DOI: 10.3892/ol.2018.8431
- Description: The cancer stem cell (CSC) theory implicates a small subpopulation of cells with stem like properties, which is responsible for tumour initiation, development and metastasis. The unique biological and functional characteristics of CSCs, widely associated with treatment resistance, indicate an association between metastasis and stemness. It was hypothesised that metastatic cell lines may be enriched in CSCs and that this would correlate with a more resistant tumour. In the present study, the SW480 and SW620 paired cell lines derived from a colon adenocarcinoma and its lymph node metastasis, respectively were compared as an in vitro model of cancer progression. Their chemosensitivity and CSC properties were investigated. A range of in vitro assays were performed, including the side population assay, ALDEFLUOR assay, tumoursphere assay and assessment of CSC associated surface phenotypes.
- Full Text:
- Date Issued: 2018
In vitro and in vivo toxicity assessment of biologically synthesized silver nanoparticles from Elaeodendron croceum:
- Odeyemi, S W, de la Mare, Jo-Anne, Edkins, Adrienne L, Afolayan, A J
- Authors: Odeyemi, S W , de la Mare, Jo-Anne , Edkins, Adrienne L , Afolayan, A J
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163488 , vital:41042 , DOI: 10.1515/jcim-2018-0184
- Description: The cytotoxic properties of nanoparticles have attracted a great deal of attention in the field of nanoscience and nanotechnology due to their small size and ability to penetrate cellular membranes.
- Full Text:
- Date Issued: 2019
- Authors: Odeyemi, S W , de la Mare, Jo-Anne , Edkins, Adrienne L , Afolayan, A J
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163488 , vital:41042 , DOI: 10.1515/jcim-2018-0184
- Description: The cytotoxic properties of nanoparticles have attracted a great deal of attention in the field of nanoscience and nanotechnology due to their small size and ability to penetrate cellular membranes.
- Full Text:
- Date Issued: 2019
Isolation, characterization and antiproliferative activity of new metabolites from the South African endemic red algal species Laurencia alfredensis
- Dziwornu, Godwin A, Caira, Mino R, de la Mare, Jo-Anne, Edkins, Adrienne L, Bolton, John J, Beukes, Denzil R, Sunassee, Suthananda N
- Authors: Dziwornu, Godwin A , Caira, Mino R , de la Mare, Jo-Anne , Edkins, Adrienne L , Bolton, John J , Beukes, Denzil R , Sunassee, Suthananda N
- Date: 2017
- Language: English
- Type: article , text
- Identifier: http://hdl.handle.net/10962/59963 , vital:27715 , https://doi:10.3390/molecules22040513
- Description: The marine red algae of the genus Laurencia have been widely studied for their structurally diverse and biologically active secondary metabolites. We report here the natural product investigation of the organic extract of a newly identified South African endemic species, Laurencia alfredensis. A sequence of column chromatography, preparative TLC and normal phase HPLC resulted in the isolation of eleven compounds comprising three labdane-type diterpenes (1-3), four polyether triterpenes (4-7), three cholestane-type ecdysteroids (8-10) and a glycolipid (11). Compounds 1-3, 5-8 and 10 have not previously been reported, while compound 9 is reported here for the first time from a natural source and the known compound 11 isolated for the first time from the genus Laurencia. The structural elucidation and the relative configuration assignments of the compounds were accomplished by extensive use of ID- and 2D-NMR, HR-ESI-MS, UV and IR spectroscopic techniques, while the absolute configuration of compound 1 was determined by single-crystal X-ray diffraction analysis. All compounds were evaluated against the MDA-MB-231 breast and HeLa cervical cancer cell lines. Compound 2 exhibited low micromolar antiproliferative activity (IC50 = 9.3 gM) against the triple negative breast carcinoma and compound 7 was similarly active (IC50 = 8.8 gM) against the cervical cancer cell line.
- Full Text:
- Date Issued: 2017
- Authors: Dziwornu, Godwin A , Caira, Mino R , de la Mare, Jo-Anne , Edkins, Adrienne L , Bolton, John J , Beukes, Denzil R , Sunassee, Suthananda N
- Date: 2017
- Language: English
- Type: article , text
- Identifier: http://hdl.handle.net/10962/59963 , vital:27715 , https://doi:10.3390/molecules22040513
- Description: The marine red algae of the genus Laurencia have been widely studied for their structurally diverse and biologically active secondary metabolites. We report here the natural product investigation of the organic extract of a newly identified South African endemic species, Laurencia alfredensis. A sequence of column chromatography, preparative TLC and normal phase HPLC resulted in the isolation of eleven compounds comprising three labdane-type diterpenes (1-3), four polyether triterpenes (4-7), three cholestane-type ecdysteroids (8-10) and a glycolipid (11). Compounds 1-3, 5-8 and 10 have not previously been reported, while compound 9 is reported here for the first time from a natural source and the known compound 11 isolated for the first time from the genus Laurencia. The structural elucidation and the relative configuration assignments of the compounds were accomplished by extensive use of ID- and 2D-NMR, HR-ESI-MS, UV and IR spectroscopic techniques, while the absolute configuration of compound 1 was determined by single-crystal X-ray diffraction analysis. All compounds were evaluated against the MDA-MB-231 breast and HeLa cervical cancer cell lines. Compound 2 exhibited low micromolar antiproliferative activity (IC50 = 9.3 gM) against the triple negative breast carcinoma and compound 7 was similarly active (IC50 = 8.8 gM) against the cervical cancer cell line.
- Full Text:
- Date Issued: 2017
Knockdown of Hop downregulates RhoC expression, and decreases pseudopodia formation and migration in cancer cell lines:
- Willmer, Tarryn, Contu, Lara, Blatch, Gregory L, Edkins, Adrienne L
- Authors: Willmer, Tarryn , Contu, Lara , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165196 , vital:41217 , DOI: 10.1016/j.canlet.2012.09.021
- Description: The Hsp90/Hsp70 organising protein (Hop) is a co-chaperone that mediates the interaction of Hsp90 and Hsp70 molecular chaperones during assembly of Hsp90 complexes in cells. Formation of Hsp90 complexes is a key intermediate step in the maturation and homeostasis of oncoproteins and several hormone receptors. In this paper, we demonstrate that knockdown of Hop decreased migration of Hs578T and MDA-MB-231 breast cancer cells. Hop was identified in isolated pseudopodia fractions; it colocalised with actin in lamellipodia, and co-sedimented with purified actin in vitro. Knockdown of Hop caused a decrease in the level of RhoC GTPase, and significantly inhibited pseudopodia formation in Hs578T cells. Our data suggest that Hop regulates directional cell migration by multiple unknown mechanisms.
- Full Text:
- Date Issued: 2013
- Authors: Willmer, Tarryn , Contu, Lara , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165196 , vital:41217 , DOI: 10.1016/j.canlet.2012.09.021
- Description: The Hsp90/Hsp70 organising protein (Hop) is a co-chaperone that mediates the interaction of Hsp90 and Hsp70 molecular chaperones during assembly of Hsp90 complexes in cells. Formation of Hsp90 complexes is a key intermediate step in the maturation and homeostasis of oncoproteins and several hormone receptors. In this paper, we demonstrate that knockdown of Hop decreased migration of Hs578T and MDA-MB-231 breast cancer cells. Hop was identified in isolated pseudopodia fractions; it colocalised with actin in lamellipodia, and co-sedimented with purified actin in vitro. Knockdown of Hop caused a decrease in the level of RhoC GTPase, and significantly inhibited pseudopodia formation in Hs578T cells. Our data suggest that Hop regulates directional cell migration by multiple unknown mechanisms.
- Full Text:
- Date Issued: 2013
Localisation of Theiler's murine encephalomyelitis virus protein 2C to the golgi apparatus using antibodies generated against a peptide region:
- Jauka, Tembisa, Mutsvunguma, Lorraine Z, Boshoff, Aileen, Edkins, Adrienne L, Knox, Caroline M
- Authors: Jauka, Tembisa , Mutsvunguma, Lorraine Z , Boshoff, Aileen , Edkins, Adrienne L , Knox, Caroline M
- Date: 2010
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165074 , vital:41206 , DOI: 10.1016/j.jviromet.2010.05.009
- Description: The picornavirus 2C protein is highly conserved and indispensible for virus replication. Polyclonal antibodies against Theiler's murine encephalomyelitis virus (TMEV) 2C protein were generated by immunisation of rabbits with a peptide comprising amino acids 31–210 of the protein. Antibodies were used to investigate the localisation of 2C in infected cells by indirect immunofluorescence and confocal microscopy. Analysis of infected cells revealed that the distribution of 2C changed during infection.
- Full Text:
- Date Issued: 2010
- Authors: Jauka, Tembisa , Mutsvunguma, Lorraine Z , Boshoff, Aileen , Edkins, Adrienne L , Knox, Caroline M
- Date: 2010
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165074 , vital:41206 , DOI: 10.1016/j.jviromet.2010.05.009
- Description: The picornavirus 2C protein is highly conserved and indispensible for virus replication. Polyclonal antibodies against Theiler's murine encephalomyelitis virus (TMEV) 2C protein were generated by immunisation of rabbits with a peptide comprising amino acids 31–210 of the protein. Antibodies were used to investigate the localisation of 2C in infected cells by indirect immunofluorescence and confocal microscopy. Analysis of infected cells revealed that the distribution of 2C changed during infection.
- Full Text:
- Date Issued: 2010
LRP1 is required for novobiocin-mediated fibronectin turnover:
- Boel, Natasha M-E, Hunter, Morgan C, Edkins, Adrienne L
- Authors: Boel, Natasha M-E , Hunter, Morgan C , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164896 , vital:41182 , DOI: 10.1038/s41598-018-29531-2
- Description: Fibronectin (FN) plays a major role in the stability and organization of the extracellular matrix (ECM). We have previously demonstrated that FN interacts directly with Hsp90, as well as showing that the Hsp90 inhibitor novobiocin results in FN turnover via a receptor mediated process. However, the receptor involved has not been previously identified. LRP1 is a ubiquitous receptor responsible for the internalisation of numerous ligands that binds both Hsp90 and FN, and therefore we investigated whether LRP1 was involved in novobiocin-mediated FN turnover.
- Full Text:
- Date Issued: 2018
- Authors: Boel, Natasha M-E , Hunter, Morgan C , Edkins, Adrienne L
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164896 , vital:41182 , DOI: 10.1038/s41598-018-29531-2
- Description: Fibronectin (FN) plays a major role in the stability and organization of the extracellular matrix (ECM). We have previously demonstrated that FN interacts directly with Hsp90, as well as showing that the Hsp90 inhibitor novobiocin results in FN turnover via a receptor mediated process. However, the receptor involved has not been previously identified. LRP1 is a ubiquitous receptor responsible for the internalisation of numerous ligands that binds both Hsp90 and FN, and therefore we investigated whether LRP1 was involved in novobiocin-mediated FN turnover.
- Full Text:
- Date Issued: 2018
Metal nanoparticles caused death of metastatic MDA-MB-231 breast cancer cells:
- Adeyemi, Oluyomi, Edkins, Adrienne L, Whiteley, Christopher
- Authors: Adeyemi, Oluyomi , Edkins, Adrienne L , Whiteley, Christopher
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164797 , vital:41173 , DOI: 10.1016/j.toxlet.2013.05.599
- Description: Available data on the toxicity of nanoparticles is a subject of controversy. The interaction of nanoparticles with biological systems including living cells has become one of the most urgent areas of collaborative research in materials science and biology. This is due to the fact that toxicity of nanomaterials are ill defined in terms of cause–effect relationships.
- Full Text:
- Date Issued: 2013
- Authors: Adeyemi, Oluyomi , Edkins, Adrienne L , Whiteley, Christopher
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/164797 , vital:41173 , DOI: 10.1016/j.toxlet.2013.05.599
- Description: Available data on the toxicity of nanoparticles is a subject of controversy. The interaction of nanoparticles with biological systems including living cells has become one of the most urgent areas of collaborative research in materials science and biology. This is due to the fact that toxicity of nanomaterials are ill defined in terms of cause–effect relationships.
- Full Text:
- Date Issued: 2013