HOP expression is regulated by p53 and RAS and characteristic of a cancer gene signature
- 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
Cytotoxic activity of marine sponge extracts from the sub-Antarctic Islands and the Southern Ocean
- Authors: Olsen, Elisabeth , De Cerf, Christopher , Dziwornu, Godwin A , Puccinelli, Eleonora , Parker-Nance, Shirley , Ansorge, Isabelle J , Samaai, Toufiek , Dingle, Laura M K , Edkins, Adrienne L , Sunassee, Suthananda N
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66300 , vital:28931 , https://doi.org/10.17159/sajs.2016/20160202
- Description: publisher version , Over the past 50 years, marine invertebrates, especially sponges, have proven to be a valuable source of new and/or bioactive natural products that have the potential to be further developed as lead compounds for pharmaceutical applications. Although marine benthic invertebrate communities occurring off the coast of South Africa have been explored for their biomedicinal potential, the natural product investigation of marine sponges from the sub-Antarctic Islands in the Southern Ocean for the presence of bioactive secondary metabolites has been relatively unexplored thus far. We report here the results for the biological screening of both aqueous and organic extracts prepared from nine specimens of eight species of marine sponges, collected from around Marion Island and the Prince Edward Islands in the Southern Ocean, for their cytotoxic activity against three cancer cell lines. The results obtained through this multidisciplinary collaborative research effort by exclusively South African institutions has provided an exciting opportunity to discover cytotoxic compounds from sub-Antarctic sponges, whilst contributing to our understanding of the biodiversity and geographic distributions of these cold-water invertebrates. Therefore, we acknowledge here the various contributions of the diverse scientific disciplines that played a pivotal role in providing the necessary platform for the future natural products chemistry investigation of these marine sponges from the sub- Antarctic Islands and the Southern Ocean. Significance: This study will contribute to understanding the biodiversity and geographic distributions of sponges in the Southern Ocean. This multidisciplinary project has enabled the investigation of marine sponges for the presence of cytotoxic compounds. Further investigation will lead to the isolation and identification of cytotoxic compounds present in the active sponge extracts. , University of Cape Town; South African Medical Research Council; National Research Foundation (South Africa); CANSA; Rhodes University; Department of Science and Technology; Department of Environmental Affairs; SANAP
- Full Text:
- Date Issued: 2016
Hsp40 Co-chaperones as drug targets: towards the development of specific inhibitors
- 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
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
Sarqaquinoic acid and related synthetic naphthoquinones inhibit the function of Hsp90
- Authors: Chiwakata, M , de la Mare, Jo-Anne , Edkins, Adrienne L , Beukes, Denzil R
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66324 , vital:28933 , https://doi.org/10.1055/s-0036-1596751
- Description: publisher version , Heat shock protein 90 (Hsp90) is of critical importance in the proper folding of numerous proteins, including those involved in cancer. Consequently, there is significant interest in the discovery and development of Hsp90 inhibitors as anticancer drugs. In this study, we investigated the ability of sargaquinoic acid (SQA) and selected naphthoquinone derivatives to inhibit Hsp90 function. SQA was isolated and purified from Sargassum incisifolium while the naphthoquinones were synthesised via a straightforward sequence incorporating a Diels-Alder reaction between benzoquinone derivatives and myrcene followed by coupling with substituted alkyl or arylamines. Hsp90 inhibition was assessed by a client protein degradation assay. At a concentration of 1µM, SQA showed almost complete inhibition of Hsp90 but only moderate antiproliferative effects (IC50 658µM) against a Hs578T breast cancer carcinoma cell line. Interestingly, the most potent synthetic aminonaphthoquinone inhibited Hsp90 function by 50% at a concentration of 1µM but showed much improved activity against the Hs578T cell line (IC50 0.32µM). Furthermore, unlike geldanamycin, none of the compounds tested upregulates Hsp70 suggesting that these compounds may bind to the C-terminal end of Hsp90.
- Full Text: false
- Date Issued: 2016
Synthesis and evaluation of substituted 4-(N-benzylamino)cinnamate esters as potential anti-cancer agents and HIV-1 integrase inhibitors
- Authors: Faridoon, H , Edkins, Adrienne L , Isaacs, Michelle , Mnkandhla, Dumisani , Hoppe, Heinrich C , Kaye, Perry T
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66289 , vital:28929 , https://doi.org/10.1016/j.bmcl.2016.05.023
- Description: publisher version , Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50 ⩾ 3.0 μM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50 ⩾ 9.6 μM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters. The potential of the ligands as HIV-1 integrase inhibitors has also been examined.
- Full Text: false
- Date Issued: 2016