Two prostate carcinoma cell lines demonstrate abnormalities in tumor suppressor genes

Rubin, Steven J.; Hallahan, Dennis E.; Ashman, Charles R.; Brachman, David; Beckett, Michael A.; Virudachalam, Subbulakshmi; Yandell, David W.; Weichselbaum, Ralph R.

doi:10.1002/jso.2930460108

Cited by 98 publications

(60 citation statements)

References 40 publications

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“…PC3 cells do not express endogenous p53 protein due to a gross deletion of one allele and a single base-pair deletion in the remaining allele (Isaacs et al, 1991;Rubin et al, 1991;Carroll et al, 1993). As expected, p53 protein expression was not detected at any time point after control virus infection (data not shown).…”

Section: Adenovirus-p53 Infection Of Vector Control and Bcl-2-overexpsupporting

confidence: 72%

A comprehensive assessment of p53-responsive genes following adenoviral-p53 gene transfer in Bcl-2-expressing prostate cancer cells

Spurgers

Coombes

Meyn³

et al. 2003

Oncogene

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Section: Adenovirus-p53 Infection Of Vector Control and Bcl-2-overexpsupporting

confidence: 72%

A comprehensive assessment of p53-responsive genes following adenoviral-p53 gene transfer in Bcl-2-expressing prostate cancer cells

Spurgers

Coombes

Meyn³

et al. 2003

Oncogene

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“…We observed that the human prostate cancer cell lines, LNCaP, DU-145 and PC-3, which differ in their status of p53, 18 expressed different levels of EMMPRIN (Fig. 1A).…”

Section: Effects Of P53 Status On Emmprin Protein Expressionmentioning

confidence: 94%

A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells

Zhu

Evans

O’Neill

et al. 2009

Cancer Biology & Therapy

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EMMPRIN, a transmembrane glycoprotein known to promote survival, invasion and metastasis of tumor cells through multiple pathways and mechanisms, has been found to be overexpressed in various types of cancer cells. Here we report that loss of the function of p53, a tumor suppressor protein that is mutated in approximately 50% of human cancers, contributes to the upregulation of EMMPRIN protein. We observed an inverse association between the activity of p53 and the level of EMMPRIN protein in several cancer cell lines. We further demonstrated that p53 is able to negatively regulate EMMPRIN protein, but downregulation of EMMPRIN by p53 is independent of repression of the EMMPRIN transcription. Furthermore, downregulation of EMMPRIN by p53 can be rescued by chloroquine, a lysosome inhibitor, but not by MG132, a proteasome inhibitor, suggesting an involvement of the lysosomal pathway in the p53-regulated degradation of EMMPRIN. Downregulation of EMMPRIN by p53 leads to a decrease in the activity of MMP-9 and an inhibition of tumor cell invasion. Our study suggests that the upregulation of EMMPRIN seen in many cancers can be attributed to, at least in part, the dysfunction of p53 and thus provides new evidence for the roles of p53 in tumor development and progression.

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“…There was also an increase in p53 protein levels at T ¼ 6 and 8 h in both cell types. It is noted that MCF-7 has wild-type p53 and wild-type Rb genes, while DU-145 contains a single mutant p53 allele encoding a double point mutant p53 protein and a mutant Rb allele with an internal in-frame deletion of exon 21 (Rubin et al, 1991;Wosikowski et al, 1995). Since BRCA1 protein was similarly lost during heating of both cell types, it is unlikely that the p53 or Rb status of these cell lines was a critical factor in the regulation of BRCA1 protein levels under heat shock conditions.…”

Section: Disappearance Of Brca1 Protein During the Heat Shock Responsementioning

confidence: 99%

Role of BRCA1 in heat shock response

et al. 2003

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The heat shock response is an evolutionarily conserved response to heat and other stresses that promotes the maintenance of key metabolic functions and cell survival. We report that exposure of human prostate (DU-145) and breast (MCF-7) cancer cells to heat (421C) caused a rapid disappearance of the breast cancer susceptibility gene-1 (BRCA1) protein, starting at E1 h after the onset of heating and slightly lagging behind the increase in heat shock protein 70 (HSP70) levels. The heat-induced loss of BRCA1 occurred at the protein level, since: (1) BRCA1 mRNA expression was unaffected; and (2) the BRCA1 protein loss was also observed in DU-145 cells that expressed exogenous wild-type BRCA1 (wtBRCA1). In addition to heat regulation of BRCA1 protein levels, we also found that BRCA1 could modulate the heat shock response. Thus, wtBRCA1 overexpressing DU-145 cell clones showed significantly decreased sensitivity to heatinduced cytotoxicity; and Brca1 mutant mouse embryo fibroblasts showed increased sensitivity to heat. The DU-145 wtBRCA1 clones also showed increased expression of the small heat shock protein HSP27; and reporter assays revealed that wtBRCA1 stimulated a two to four-fold increase in HSP27 promoter activity, consistent with its ability to upregulate HSP27 mRNA and protein levels. In studies using epitope-tagged truncated BRCA1 proteins, the ability to stimulate the HSP27 promoter and to mediate heat-induced degradation required the aminoterminus but not the carboxyl-terminus of BRCA1. Although the heat-induced loss of BRCA1 appeared to be due to protein degradation, various protein metabolic agents (or combinations) failed to block this event, including: MG132 (a 26S proteasomal inhibitor), Nacetyl-leucyl-leucyl-norleucinal (a calpain inhibitor), z-VAD-fmk (a pan-caspase inhibitor), and ammonium chloride and chloroquine (which stabilize lysosomes). These findings suggest that in addition to its other functions, BRCA1 may participate in mammalian heat shock response pathways.

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Two prostate carcinoma cell lines demonstrate abnormalities in tumor suppressor genes

Cited by 98 publications

References 40 publications

A comprehensive assessment of p53-responsive genes following adenoviral-p53 gene transfer in Bcl-2-expressing prostate cancer cells

A comprehensive assessment of p53-responsive genes following adenoviral-p53 gene transfer in Bcl-2-expressing prostate cancer cells

A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells

Role of BRCA1 in heat shock response

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