BRCA1 signals ARF-dependent stabilization and coactivation of p53

Somasundaram, Kumaravel; MacLachlan, Timothy K.; Burns, Timothy F.; Sgagias, Magdalene K.; Cowan, Kenneth H.; Weber, Barbara; El‐Deiry, Wafik S.

doi:10.1038/sj.onc.1203284

Cited by 65 publications

(63 citation statements)

References 34 publications

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“…[22][23][24] A375 (melanoma), MCF7 (breast carcinoma), PA-1 (ovarian carcinoma), HepG2 (hepatic carcinoma), U373MG (glioblastoma), SkBr3 (breast carcinoma), C33A (cervical carcinoma) and T47D (breast carcinoma) were grown in DMEM (Sigma) supplemented with 10% FBS. Human normal lung fibroblasts (HEL 299) and immortalized keratinocytes (HaCaT) were obtained from NCCS, Pune, India.…”

Section: Tumor Cell Lines and Culture Conditionsmentioning

confidence: 99%

p73β-expressing recombinant adenovirus: a potential anticancer agent

et al. 2005

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Tumor suppressor p53-based gene therapy strategy is ineffective in certain conditions. p73, a p53 homologue, could be a potential alternative gene therapy agent as it has been found to be an important determinant of chemosensitivity in cancer cells. Previously, we have reported the generation of a replication-deficient adenovirus expressing p73b (Ad-p73). In this study, we evaluated the therapeutic potential of Ad-p73 against a panel of cancer cells (n ¼ 12) of different tissue origin. Ad-p73 infected all the cell lines tested very efficiently resulting in several-fold increase in p73b levels, which is also functional as it activated the known target gene p21 WAF1/CIP1 . Infection with Ad-p73 resulted in potent cytotoxicity in all the cell lines tested. The mechanism of p73-induced cytotoxicity in these cell lines is found to be due to a combination of cell cycle arrest and induction of apoptosis. In addition, exogenous overexpression of p73 by Ad-p73 infection increased the chemosensitivity of cancer cells by many fold to commonly used drug adriamycin. Moreover, Ad-p73 is more efficient than Ad-p53 in enhancing the chemosensitivity of mutant p53 harboring cells. Furthermore, Ad-p73 infection did not induce apoptosis in human normal lung fibroblasts (HEL 299) and human immortalized keratinocytes (HaCaT). These results suggest that Ad-p73 is a potent cytotoxic agent specifically against cancer cells and could be developed as a cancer gene therapy agent either alone or in combination with chemotherapeutic agents.

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Section: Tumor Cell Lines and Culture Conditionsmentioning

confidence: 99%

p73β-expressing recombinant adenovirus: a potential anticancer agent

et al. 2005

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“…[29][30][31] HCT116 p53 À/À , which lacks both copies of p53, was kindly provided by Dr. B. Vogelstein, Johns Hopkins University. 32 H460 NEO, H460 E6, HCT116 NEO and HCT116 E6 cell lines were kindly provided by Dr. W.S.…”

Section: Cell Lines Transfections and Reporter Assaysmentioning

confidence: 99%

“…31 To identify the role of p14 ARF in p53 stabilization by NaB, we compared the ability of NaB to stabilize p53 in human cell lines differing in their p14 ARF status. The human breast carcinoma cell line, MCF7, lacks p14 ARF expression.…”

Section: Nab Induces P53-mediated Transactivationmentioning

confidence: 99%

“…46 Human lung carcinoma cell line H460 and colon carcinoma cell line HCT116 both carry p14 ARF . 31 Adriamycin, a DNA damaging agent, was used as control because it does not require p14 ARF to stabilize p53. 31 Both H460 and HCT116 cells stabilized p53 in response to FIGURE 2 -NaB treatment stabilizes p53 in a p14 ARF -dependent manner and activates p21 WAF1/CIP1 .…”

Section: Nab Induces P53-mediated Transactivationmentioning

confidence: 99%

“…31 Adriamycin, a DNA damaging agent, was used as control because it does not require p14 ARF to stabilize p53. 31 Both H460 and HCT116 cells stabilized p53 in response to FIGURE 2 -NaB treatment stabilizes p53 in a p14 ARF -dependent manner and activates p21 WAF1/CIP1 . H460, HCT116 and MCF7 cells were treated with adriamycin (0.2 mg/ml) or NaB (1 mM in A) for 24 hr.…”

Section: Nab Induces P53-mediated Transactivationmentioning

confidence: 99%

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Role of p53 status in chemosensitivity determination of cancer cells against histone deacetylase inhibitor sodium butyrate

Joseph

Wajapeyee

Somasundaram

2005

Intl Journal of Cancer

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Histone deacetylases inhibitors (HDIs) induce growth arrest and apoptosis in a variety of human cancer cells. Sodium butyrate (NaB), a histone deacetylase inhibitor, has been shown to cause a G 1 cell cycle arrest by inducing p21 WAF1/CIP1 in a p53-independent manner. In this report, we present evidence for activation of p53 pathway by NaB and its role in the NaB-mediated growth suppression. Addition of NaB increased the levels of p53 involving a p14 ARF -dependent post-transcriptional mechanism. NaB induced p53 is functional as it activated p53-specific reporter, induced the level of p21 WAF1/CIP1 , inhibited cellular DNA synthesis and induced apoptosis. By using HPV 16 E6 stable transfectants as well as p53 null cancer cells, we show that NaB suppresses the growth of WT p53 containing cells more efficiently. NaB inhibited DNA synthesis to similar extent both in the presence and absence of p53. However, NaB treatment lead to a major G 2 /M arrest of cells in the presence of p53, while cells without wild-type p53 accumulated mainly in G 1 phase of the cell cycle. Furthermore, apoptosis induction by NaB is greatly reduced in the absence of p53. These results suggest that p53 pathway mediates in part growth suppression by NaB and the p53 status may be an important determinant of chemosensitivity in HDI based cancer chemotherapy. ' 2005 Wiley-Liss, Inc.Key words: Histone deacetylase inhibitors; sodium butyrate; p53; apoptosis; growth arrest Chromatin remodeling plays an important role in transcriptional regulation. Evidence suggest that acetylation and deacetylation of histones and/or nonhistone proteins play significant roles in chromatin remodeling and thus in the regulation of transcription. 1,2 Consequently, histone acetyl transferases (HATs) and histone deacetylases (HDACs) are emerging as important molecules in transcriptional regulation. Histone deacetylases inhibitors (HDIs) are promising agents for anticancer therapy as they exhibit strong antitumor activities in vivo with low toxicity in preclinical studies. HDIs belong to a heterogenous class of compounds that includes derivatives of short chain fatty acids, hydroxamic acids, cyclic tetrapetides and benzamides.Sodium butyrate (NaB), a short chain fatty acid, is a histone deacetylase inhibitor and is produced in the colonic lumen as a consequence of microbial degradation of dietary fibers. 3,4 Sodium butyrate and other deacetylase inhibitors are not growth inhibitory to normal cells. 5,6 The growth inhibitory effect of NaB against cancer cells has been attributed to its ability to induce cell cycle arrest, differentiation and apoptosis. 7-10 NaB induced cell cycle arrest and differentiation has been correlated with its ability to induce p21 WAF1/CIP1 in a p53-independent manner 11-15 and modulate levels of cyclin D1, 12,16,17 cdc2, 17 cdk2 12,18 and proliferating cell nuclear antigen (PCNA). 19 However, the mechanism of apoptosis induction by NaB is not clearly understood. Acetylation of nontranscriptional targets such as nonhistone proteins like tubulin...

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Breast cancer gene 1 (BRCA1): Role in cell cycle regulation and DNA repair—perhaps through transcription

Somasundaram

2003

J of Cellular Biochemistry

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Mutations of BRCA1 gene are associated with more than half the cases of hereditary breast cancer. Breast cancer formation in BRCA1 mutation carriers is generally accompanied by loss of the wild-type allele, suggesting that BRCA1 protein may function as a tumor suppressor. The human BRCA1 gene encodes a nuclear protein of 1863 amino acids. Although several lines of evidences suggest that BRCA1 protein may have a role to play in cell cycle regulation, DNA repair, and other processes, the exact mechanism of functioning by BRCA1 protein is not clear. Recent evidences from several laboratories suggest that BRCA1 may regulate the expression of many genes like p21(WAF1/CIP1), Gadd45, Cyclin B1, DBB2, XPC, 14-3-3ó and others at the level of transcription. These BRCA1-regulated gene products have been implicated directly or indirectly in cell cycle regulation and DNA repair. Thus a plausible model is proposed in which BRCA1 protein may bring its effects on cell cycle and DNA repair through its ability to modulate gene expression at the level of transcription.

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BRCA1 signals ARF-dependent stabilization and coactivation of p53

Cited by 65 publications

References 34 publications

p73β-expressing recombinant adenovirus: a potential anticancer agent

p73β-expressing recombinant adenovirus: a potential anticancer agent

Role of p53 status in chemosensitivity determination of cancer cells against histone deacetylase inhibitor sodium butyrate

Breast cancer gene 1 (BRCA1): Role in cell cycle regulation and DNA repair—perhaps through transcription

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