Lost in Transcription: p21 Repression, Mechanisms, and Consequences

Gartel, Andrei L.; Radhakrishnan, Senthil K.

doi:10.1158/0008-5472.can-04-3995

Cited by 737 publications

(638 citation statements)

References 69 publications

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“…Among various cell cycle checkpoint proteins participating in the evolution of the cell cycle, cyclin A‐CDK1 complex and cyclin A‐CDK2 are required for passage into the late S/G2 phase while the cyclin B1‐CDK1 complex is involved in G2/M transition 42, 43, 44. Activity of these CDKs is regulated by inhibitor p21 45. Our data showed that inhibition of cIAP1 causes a drastic decrease in cyclin B1‐CDK1 and cyclin A‐CDK1/2 expression but a dramatic increase in their CKI p21 (Figures 2C and 3C).…”

Section: Discussionmentioning

confidence: 99%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small‐molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase‐3/7‐activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1‐CDK1 and cyclin A‐CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent‐G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1‐mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.

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Section: Discussionmentioning

confidence: 99%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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“…However, it is possible that the p21 WAF1/CIP1 upregulation event is not linked at all to the enhanced apoptotic effect. Although p21 WAF1/CIP1 is known mostly as an inhibitor of apoptosis (Gartel and Tyner, 2002), in some other cases it can promote apoptosis (Gartel, 2005;Gartel and Radhakrishnan, 2005). Further studies that include p21 WAF1/CIP1 knockdown by siRNA and isogenic cells modified to lack p21 WAF1/CIP1 expression could provide a direct answer for the exact role of p21 WAF1/CIP1 in enhancing the apoptotic effect of HDAC inhibitors by DAC pretreatment.…”

Section: Discussionmentioning

confidence: 99%

p21WAF1/CIP1 induction by 5-azacytosine nucleosides requires DNA damage

et al. 2008

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Decitabine (DAC) and 5-azacitidine have recently been approved for the treatment of myelodysplastic syndrome. The pharmacodynamic effects of DAC and 5-azacitidine outside their known activity as inhibitors of DNA methyltransferases (DNMTs) require further investigation. The purpose of this study was to investigate the effect of DAC on the expression of p21 WAF1/CIP1 , a gene with a putative CpG island surrounding its promoter region. Promoter methylation analysis of p21 WAF1/CIP1 in leukemia cells revealed the absence of CpG methylation. However, DAC upregulated p21 WAF1/CIP1 expression in a dosedependent manner (ED 50 ¼ 103.34 nM) and induced G2/M cell cycle arrest in leukemia cells. Sequential application of DAC followed by different histone deacetylase inhibitors induced expression of p21 WAF1/CIP1 synergistically. Upregulation of p21 WAF1/CIP1 paralleled DAC-induced apoptosis (ED 50 ¼ 153 nM). Low doses of DAC induced c-H2AX expression (ED 50 ¼ 16.5 nM) and upregulated p21 WAF1/CIP1 in congenic HCT 116 colon cancer cells in a DNMT-independent and p53-dependent fashion. Inhibition of p53 transactivation by pifithrin-a or the kinase activity of ATM by either the specific ATM inhibitor KU-5593 or caffeine abrogated p21 WAF1/CIP1 upregulation, indicating that DAC upregulation of p21 WAF1/CIP1 was p53-and ATM-dependent in leukemia cells. In conclusion, DAC upregulates p21 WAF1/CIP1 in DNMT-independent manner via the DNA damage/ATM/ p53 axis.

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Section: Introductionmentioning

confidence: 99%

“…The regulation of p21 occurs primarily at the transcriptional and post-transcriptional levels (Gartel and Radhakrishnan, 2005). p21 was originally identified as a downstream mediator of p53-induced growth arrest, but now it is well established that the p21 expression is controlled by diverse mechanisms in both p53-dependent or -independent manner (Gartel and Radhakrishnan, 2005). In addition to p53-binding to the distal region of p21 promoter, studies have shown that Sp1 family of transcription factors (Sp1 and Sp3) binds to six GC-rich motifs present in the proximal promoter of the human p21 gene (Koutsodontis et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Mutation of p53 has been recognized as one of the major events in carcinogenesis, in more than 50% of human cancers including skin cancer (Wanner et al, 2002), whereas the mutation of p21 in human cancers is rare (Gartel and Radhakrishnan, 2005). Therefore, agents that could activate p21 through a p53-independent mechanism like Sp1-mediated transcriptional activation might contribute to chemotherapy or prevention of cancer as molecular-targeted drug candidate (Patel et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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A novel antioxidant 3-O-Caffeoyl-1-methylquinic acid enhances ultraviolet A-mediated apoptosis in immortalized HaCaT keratinocytes via Sp1-dependent transcriptional activation of p21WAF1/Cip1

et al. 2006

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It has become clear that ultraviolet A (UVA) radiation from the solar spectrum is a major environmental challenge to the skin. This necessitates developing novel mechanism-based agents capable of ameliorating UVAinduced effects in the skin. We recently described a novel antioxidant, 3-O-Caffeoyl-1-methylquinic acid (MCGA3) from leaves of bamboo. Here, we investigated the photochemopreventive effects of MCGA3 against UVAmediated apoptosis in immortalized HaCaT keratinocytes. Pretreatment of MCGA3 rendered cells more sensitive to subsequent UVA irradiation-induced apoptosis as well as completely reversed UVA-induced sustained phosphorylation of extracellular signal-regulated kinase 1/2 and protein kinase Ca, downregulation of p21, and reactive oxygen species generation. Interestingly, MCGA3 itself effectively induced p21 protein and mRNA levels. Silencing of p21 by RNA interference revealed a pivotal role of p21 in generating G 1 -S arrest and in enhancing UVA-mediated apoptosis. Transcriptional activation of p21 by MCGA3 was mediated through the proximal region of multiple Sp1 sites regardless of p53-binding site in p21 promoter, and this effect was augmented by desferroioxamine, an iron chelating agent. Additional studies suggested that iron chelation-driven hypoxia by MCGA3 may function in activation of p21. MCGA3 could be a useful agent to prevent photocarcinogenesis via apoptotic elimination of p53 mutant and DNA-repair defective cells caused by UVA radiation.

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Lost in Transcription: p21 Repression, Mechanisms, and Consequences

Cited by 737 publications

References 69 publications

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

p21WAF1/CIP1 induction by 5-azacytosine nucleosides requires DNA damage

A novel antioxidant 3-O-Caffeoyl-1-methylquinic acid enhances ultraviolet A-mediated apoptosis in immortalized HaCaT keratinocytes via Sp1-dependent transcriptional activation of p21WAF1/Cip1

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