Role of p21WAF1 in the Cellular Response to UV

Fotedar, Rati; Bendjennat, Mourad; Fotedar, Arun

doi:10.4161/cc.3.2.658

Cited by 79 publications

(77 citation statements)

References 55 publications

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“…p21 is a mediator of cell cycle arrest upregulated via multiple pathways in response to damaged DNA. 35,46,47 Conclusively, we observed an upregulation of p21 in MDA-MB 231 cells in response to doxorubicin treatment, which was again strictly dependent on FHL2 expression. Investigations concerning the mechanism of FHL2-dependent p21 induction in MDA-MB 231 cells indicated that p21 upregulation occurred in a p53 independent manner, possibly reflecting the fact that these cells do not express wild-type p53, but high levels of a mutated p53 variant.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 60%

“…35 To test whether FHL2 expression is also required for DNA damage-mediated p21 upregulation, we induced DNA damage by treating shSCR and shFHL2 cells with doxorubicin for 16 h and analyzed the p21 protein levels in the respective cells. Again, while untreated shSCR cells expressed the p21 protein, no p21 induction could be observed in the untreated shFHL2 cells (Fig.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

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FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Martin¹,

Kleiber²,

Wixler³

et al. 2007

Cell Cycle

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© 2 0 0 7 L A N D E S B I O S C I E N C E . D O N O T D I S T R I B U T E .[Cell Cycle 6:14, 1779-1788, 15 ABSTRAcTThe transcriptional cofactor FHL2 interacts with a broad variety of transcription factors and its expression is often deregulated in various types of cancer. Here we analyzed for the first time the molecular function of FHL2 in breast cancer. FHL2 is overexpressed in almost all human mammary carcinoma samples tested but not in normal breast tissues and only low levels of FHL2 expression were present in four premalignant ductal carcinoma in situ (DCIS). Cell cycle analysis revealed an upregulation of endogenous FHL2 towards G 2 /M in MDA-MB 231 cells and an accelerated G 2 /M transition when FHL2 expression was suppressed in these cells. In search for G 2 /M specific target genes regulated by FHL2, we found that expression of the cell cycle inhibitor p21 Cip1/Waf1 (hereafter p21) is dependent on FHL2 in MDA-MB 231 breast cancer cells. Downregulation of FHL2 by shRNA abrogated the cell cycle dependent upregulation of p21 as well as the induction of p21 in response to treatment with the DNA damaging agent doxorubicin. FHL2-dependent p21 expression occurs in a p53-independent manner and p21 expression can be downregulated by specific inhibition of mitogen-activated protein kinases (MAPKs), implicating an involvement of MAPK signaling in this regulation. Analysis of FHL2 contribution to the MAPK signaling identified FHL2 as an important downstream effector of MAPKs in breast cancer cells, capable of transactivating endogenous AP1 target genes as well as AP1 dependent reporter genes. Finally, downregulation of FHL2 reduces the ability of MDA-MB 231 cells to form colonies in soft agar, while FHL2 overexpression enhances colony formation of breast cancer cells. Thus, our findings indicate that overexpression of the transcriptional cofactor FHL2 contributes to breast cancer development by mediating transcriptional activation of MAPK target genes known to be involved in cancer progression, such as p21.

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Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 60%

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Martin¹,

Kleiber²,

Wixler³

et al. 2007

Cell Cycle

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show abstract

“…It is well known that some DNA-damaging agents, such as ultraviolet and ionizing radiations, can target P21 CIP1 protein for degradation immediately after DNA damage (Fotedar et al, 2004;Hill et al, 2008). For this reason, in some experimental conditions, increased expression of P21 CIP1 cannot be detected after P53 activation.…”

Section: Brg1 and Senescence Of Mesenchymal Stem Cells N Alessio Et Almentioning

confidence: 99%

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

et al. 2010

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We focused our attention on brahma-related gene 1 (BRG1), the ATPase subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, and analyzed its role in mesenchymal stem cell (MSC) biology. We hypothesized that deviation from the correct concentration of these proteins, which act at the highest level of gene regulation, may be deleterious for cells. We wanted to know what would happen if a cell had to cope with altered regulation of gene expression, either by upregulation or downregulation of BRG1. We assumed that cells would try to restore homeostasis or, alternatively, that the event could trigger senescence/apoptosis phenomena. To this end, in MSCs, we silenced BRG1gene. Knockdown of BRG1 expression induced a significant increase in senescent cells and decrease in apoptotic cells. It is interesting that BRG1 downregulation also induced an increase in heterochromatin. At the molecular level, these phenomena were associated with activation of retinoblastoma-like protein 2 (RB2)/P130-and P53-related pathways. Senescence was accompanied by reduced expression of some stemness-related genes. This is consistent with our previous research, which showed that BRG1 upregulation by ectopic expression also induced senescence processes. Together, these data suggest that BRG1 belongs to a class of genes whose expression is tightly regulated; hence, subtle alterations in BRG1 activity seem to negatively affect mechanisms regulating chromatin status and, in turn, impair cellular physiology.

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“…However, the regulatory activities of p21 are complex, and involve DNA repair activities other than TLS. 50 Therefore, additional studies are needed to fully elucidate the physiologically relevant effects of p21 on TLS.…”

Section: Model For the Regulation Of Tls By P53 And P21mentioning

confidence: 99%

Keeping Mammalian Mutation Load in Check: Regulation of the Activity of Error-Prone DNA Polymerases by p53 and p21

Livneh

2006

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=3193 Extra View KEY WORDS Keeping Mammalian Mutation Load in CheckRegulation of the Activity of Error-prone DNA Polymerases by p53 and p21 ABSTRACTTo overcome DNA lesions that block replication the cell employs translesion DNA synthesis (TLS) polymerases, a group of low fidelity DNA polymerases that have the capacity to bypass a wide range of DNA lesions. This TLS process is also termed error-prone repair, due to its inherent mutagenic nature. We have recently shown that the tumor suppressor p53 and the cell cycle inhibitor p21 are global regulators of TLS. When these proteins are missing or nonfunctional, TLS gets out of control: its extent increases to very high levels, and its fidelity decreases, causing an overall increase in mutation load. This may be explained by the loss of selectivity in the bypass of specific DNA lesions by their cognate specialized polymerases, such that lesion bypass continues to a maximum, regardless of the price paid in increased mutations. The p53 and p21 proteins are also required for efficient UV light-induced monoubiquitination of PCNA, which is consistent with a model in which this modification of PCNA is necessary but not sufficient for the normal activity of TLS. This regulation suggests that TLS evolved in mammals as a system that balances gain in survival with a tolerable mutational cost, and that disturbing this balance causes a potentially harmful increase in mutations, which might play a role in carcinogenesis.

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Role of p21WAF1 in the Cellular Response to UV

Abstract: View related articles Citing articles: 3 View citing articles © L a n d e s B i o s c i e n c e 2 0 0 4 . N o t f o r d i s t r i b u t i o n .

Cited by 79 publications

References 55 publications

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

Keeping Mammalian Mutation Load in Check: Regulation of the Activity of Error-Prone DNA Polymerases by p53 and p21

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