p53-dependent induction of heat shock protein 27 (HSP27) expression

Gao, Cong-Zhang; Zou, Zhiqiang; Xu, Linda; Moul, Judd W.; Seth, Prem; Srivastava, Shiv

doi:10.1002/1097-0215(20001015)88:2<191::aid-ijc7>3.0.co;2-a

Cited by 20 publications

(14 citation statements)

References 22 publications

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“…The Hsp27 protein, which lies downstream of p38MAPK, is a member of the heat-shock class of proteins which play pivotal roles in a variety of cellular processes such as stress and apoptosis. Hsp27 is of particular interest to our laboratory because it has been described to have anti-apoptotic functions[8] and lies downstream of p53 [9], similar to what we and others have described for p21. [10-12].…”

Section: Resultsmentioning

confidence: 79%

“…Using proteomic and then immunoblotting analysis in RCC, we have confirmed that phospho (but not native) Hsp27 is elevated in ccRCC in a parallel manner to p21. These findings were of special interest, since both proteins are induced by p53 [9], and there are reports that elevated levels of Hsp27[20], as p21[5], are associated with decreased patient survival. These data are also consistent with our pathway analysis showing that the p53 pathway is altered in ccRCC (Table 4).…”

Section: Discussionmentioning

confidence: 99%

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Pathway analysis of kidney cancer using proteomics and metabolic profiling

et al. 2006

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Background: Renal cell carcinoma (RCC) is the sixth leading cause of cancer death and is responsible for 11,000 deaths per year in the US. Approximately one-third of patients present with disease which is already metastatic and for which there is currently no adequate treatment, and no biofluid screening tests exist for RCC. In this study, we have undertaken a comprehensive proteomic analysis and subsequently a pathway and network approach to identify biological processes involved in clear cell RCC (ccRCC). We have used these data to investigate urinary markers of RCC which could be applied to high-risk patients, or to those being followed for recurrence, for early diagnosis and treatment, thereby substantially reducing mortality of this disease.

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Section: Resultsmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Pathway analysis of kidney cancer using proteomics and metabolic profiling

et al. 2006

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“…Although HSF-1 is considered to be the transcription factor responsible for Hsp27 induction, other factors can also induce Hsp27 (54). For example, wild type p53, a proapoptotic protein, was reported to induce Hsp27 expression in prostate cancer cells but not by mutant p53.…”

Section: Discussionmentioning

confidence: 99%

Forced Expression of Heat Shock Protein 27 (Hsp27) Reverses P-Glycoprotein (ABCB1)-mediated Drug Efflux and MDR1 Gene Expression in Adriamycin-resistant Human Breast Cancer Cells

Kanagasabai¹,

Krishnamurthy²,

Druhan

et al. 2011

Journal of Biological Chemistry

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Mutant p53 accumulation has been shown to induce the multidrug resistance gene (MDR1) and ATP binding cassette (ABC)-based drug efflux in human breast cancer cells. In the present work, we have found that transcriptional activation of the oxidative stress-responsive heat shock factor 1 (HSF-1) and expression of heat shock proteins, including Hsp27, which is normally known to augment proteasomal p53 degradation, are inhibited in Adriamycin (doxorubicin)-resistant MCF-7 cells (MCF-7/adr). Such an endogenous inhibition of HSF-1 and Hsp27 in turn results in p53 mutation with gain of function in its transcriptional activity and accumulation in MCF-7/adr. Also, lack of HSF-1 enhances nuclear factor B (NF-B) DNA binding activity together with mutant p53 and induces MDR1 gene and P-glycoprotein (P-gp, ABCB1), resulting in a multidrug-resistant phenotype. Ectopic expression of Hsp27, however, significantly depleted both mutant p53 and NF-B (p65), reversed the drug resistance by inhibiting MDR1/P-gp expression in MCF-7/ adr cells, and induced cell death by increased G 2 /M population and apoptosis. We conclude from these results that HSF-1 inhibition and depletion of Hsp27 is a trigger, at least in part, for the accumulation of transcriptionally active mutant p53, which can either directly or NF-B-dependently induce an MDR1/P-gp phenotype in MCF-7 cells. Upon Hsp27 overexpression, this pathway is abrogated, and the acquired multidrug resistance is significantly abolished so that MCF-7/adr cells are sensitized to Dox. Thus, clinical alteration in Hsp27 or NF-B level will be a potential approach to circumvent drug resistance in breast cancer.Development of a multidrug-resistant phenotype is a major obstacle to the successful treatment of breast cancer (1, 2). There are two major pathways by which cancer cells acquire drug resistance, drug efflux and direct suppression of apoptosis. Drug efflux is due to increased plasma membrane accumulation of various ATP-binding cassette (ABC) 2 transporters, including ABCB1, also known as P-glycoprotein (P-gp), which extrude the internalized drugs from the cancer cells (3-5). Various approaches have been reported to overcome the drug efflux, including pharmacological inhibition of ABCs and modulation of endogenous regulators of MDR1 (6). Drug resistance is also acquired via direct suppression of apoptotic pathways due to accumulation of mutant p53 (mutp53) with "gain of function" (7, 8) and increased expression of antiapoptotic proteins, such as BCl-2 (4). In addition to abrogating the proapoptotic function of wild type p53 (wtp53), these p53 missense mutations have been shown to have unusual gain of function properties both in vitro and in vivo (9 -11). Recent studies have established a link between these two pathways of drug resistance (12).Mutant p53 has been found to be the prominent common mediator of both pathways (11). Wild type p53 is generally known to repress the expression of the MDR1 gene, which codes for the ABC protein P-gp through interaction with basal transcription facto...

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“…1B). These two polypeptides were identified as the p53-inducible gene products 14-3-3 (27) and HSP27 (28) (Table I), and their downregulation in Barrett's epithelium suggests that p53 may be attenuated as a transcription factor. Other proteins of interest identified by this method include galectin-7, annexin-1, and calgranulin A (Table II).…”

Section: Identification Of a Novel Polypeptide Overproduced In Barretmentioning

confidence: 99%

The Barrett’s Antigen Anterior Gradient-2 Silences the p53 Transcriptional Response to DNA Damage

Pöhler

Craig

Cotton

et al. 2004

Molecular & Cellular Proteomics

131

174

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The esophageal epithelium is subject to damage from bile acid reflux that promotes normal tissue injury resulting in the development of Barrett's epithelium. There is a selection pressure for mutating p53 in this preneoplastic epithelium, thus identifying a physiologically relevant model for discovering novel regulators of the p53 pathway. Proteomic technologies were used to identify such p53 regulatory factors by identifying proteins that were overexpressed in Barrett's epithelium. A very abundant polypeptide selectively expressed in Barrett's epithelium was identified as anterior gradient-2. Immunochemical methods confirmed that anterior gradient-2 is universally up-regulated in Barrett's epithelium, relative to normal squamous tissue derived from the same patient. Cancer development is a multistep process involving sequential mutation in oncogenes and tumor suppressor genes that give selective advantage to the evolving cancer cells. The major clinical models that are giving novel molecular mechanistic insight into the multistep evolution of human neoplasia include colorectal and esophageal cancer. Colorectal cancer progression is perhaps the most well-characterized model whereby cancer development evolves through histopathological stages termed dysplasia, adenoma, and carcinoma, which can eventually metastasize. Classic molecular studies in colorectal cancer have indicated that RAS and APC mutations occur earlier in this progression sequence, while p53 mutations occur relatively later (1). Additional modifying factors include genome instability, (2), DNA methylation (3), and associated epigenetic changes in the expression of regulatory genes that can have profound effects on cancer incidence (4).Esophageal adenocarcinoma cancer progression also proceeds through a set of morphological intermediates termed metaplasia and dysplasia, which are collectively called Barrett's esophagus or Barrett's epithelium (5, 6). Barrett's epithelium is thought to develop as an adaptive response following exposure to gastric and duodenal contents refluxed into the esophagus. Barrett's epithelium is a premalignant lesion, and although the progression from Barrett's cell types to adenocarcinoma is not inevitable, the risk is estimated at an increase of 30-to 125-fold as compared with the normal population (7-9) The incidence of Barrett's epithelium has dramatically increased over the last decade; however, more alarming is the parallel increase in adenocarcinoma of the esophagus over a similar period of time (10). Barrett's epithelium being hyperproliferative is believed to be a fertile field for malignant transformation, and such early premalignant lesions produce biological and genetic heterogeneity as seen in previous studies by p53 mutations, aneuploidy, and abnormal methylation resulting in stepwise changes in differentiation, proliferation, and apoptosis (11). However, the environmental, genetic, and metabolic factors that regulate stress responses in normal and Barrett's epithelium, as well as the associated transformation o...

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p53-dependent induction of heat shock protein 27 (HSP27) expression

Cited by 20 publications

References 22 publications

Pathway analysis of kidney cancer using proteomics and metabolic profiling

Pathway analysis of kidney cancer using proteomics and metabolic profiling

Forced Expression of Heat Shock Protein 27 (Hsp27) Reverses P-Glycoprotein (ABCB1)-mediated Drug Efflux and MDR1 Gene Expression in Adriamycin-resistant Human Breast Cancer Cells

The Barrett’s Antigen Anterior Gradient-2 Silences the p53 Transcriptional Response to DNA Damage

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