The impact of R213 mutation on p53-mediated p21 activity

Zhang, Yan; Zhang, Yanjun; Zhao, Hong; Zhai, Qiaoli; Zhang, Ye; Shen, Yufei

doi:10.1016/j.biochi.2013.12.017

Cited by 21 publications

(22 citation statements)

References 18 publications

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“…The identified homozygous p53 mutation thus clearly explains apoptosis resistance in ESS-1 cells as in the case of complete p53-deficiency, no physical interactions or transcriptional activities can take place at all. Alternatively, in case of undetectable p53 protein, it was previously reported that the R213X mutation disrupted the efficiency of p53 transactivation by its inability to bind consensus binding sequences of p53 in the regulatory region of the p21WAF gene [35]. In addition, this mutation was also found to be a dominant negative p53 variant which suppresses the endogenous wild-type function [36].…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism leading to SAHA-induced autophagy in tumor cells: evidence for a p53-dependent pathway

et al. 2016

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BackgroundRecent studies indicated that histone deacetylase inhibitors (HDACi), a class of anticancer agents, are in addition to their ability of apoptosis induction also capable of provoking autophagy. Promoted by the treatment of malignant uterine sarcoma cells with the HDACi suberoylanilide hydroxamic acid (SAHA), we previously demonstrated predominant dose-dependent activation of autophagy in ESS-1 cells, but prevalent induction of apoptosis in MES-SA cells.MethodsIn order to extend our previous studies, SAHA-treated ESS-1 and MES-SA cells were monitored for protein expression to reveal differences in known markers of apoptosis explaining the different cytotoxic responses. Further analysis of the identified candidate protein included cell rescue experiments by gene transfer followed by subsequent screening of cells for induction of apoptosis and autophagy by immunoblotting, caspase activity as well as LC3 and MDC/PI staining. LDH release assays were performed to assess the amount of cell-mediated cytotoxicity.ResultsIn our search for responsible autophagic regulatory genes upstream of mammalian target of rapamycin (mTOR), we now discovered that, in contrast to MES-SA cells, a TP53-637C>T nonsense mutation located in the transactivating domain of the oncogenic suppressor p53 causes loss of its protein and consequently reduced PUMA induction in ESS-1 cells. Upon re-introduction of wild-type TP53, SAHA-treated ESS-1 cells underwent immediate apoptotic cell death as supported by upregulation of PUMA and caspase-9 as well as by activation of caspases-3 and -7 and PARP-1 cleavage. Concurrent downregulation of autophagy was noticed by upregulated mTor and phospho-mTOR expression as well as monitoring autophagosome formation employing LC3 and MDC staining. Previously, cytoplasmic master regulatory activities of the oncogenic suppressor p53 in inhibiting autophagy and triggering apoptosis were unravelled. Accordingly, p53-deficiency could explain both, the previously documented apoptosis resistance and prevailing SAHA-induced autophagy in ESS-1 cells. Using MES-SA cells with RNAi-silenced p53 expression and several p53-deficient tumor cell lines undergoing SAHA-induced autophagy, we could generally validate our finding suggesting an inhibitory role for p53 in the autophagic pathway in response to SAHA treatment.ConclusionsConclusively, these results could identify cytoplasmic p53 protein as a molecular switch that directly mediates the cytotoxic response of SAHA and thus open new therapeutic avenues.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanism leading to SAHA-induced autophagy in tumor cells: evidence for a p53-dependent pathway

et al. 2016

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“…During the responses to DNA damage, P53 was induced and specifically bound its consensus binding sequences in the regulatory region of p21 (wild-type p53-activated fragment) to trans-activate the genes, causing prevention of cell cycle progression via arresting cells in the G1/s [3, 4]. In addition to inhibiting CDK activity, P21 binds to proliferating cell nuclear antigen (PCNA) and prevents it from activation of DNA polymerase, an activity required for DNA replication and repair.…”

Section: Introductionmentioning

confidence: 99%

Specific up-regulation of p21 by a small active RNA sequence suppresses human colorectal cancer growth

et al. 2017

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The double stranded small active RNA (saRNA)- p21-saRNA-322 inhibits tumor growth by stimulating the p21 gene expression. We focused our research of p21-saRNA-322 on colorectal cancer because 1) p21 down-regulation is a signature abnormality of the cancer, and 2) colorectal cancer might be a suitable target for in situ p21-saRNA-322 delivery. The goal of the present study is to learn the activity of p21-saRNA-322 in colorectal cancer. Three human colorectal cancer cell lines, HCT-116, HCT-116 (p53–/−) and HT-29 were transfected with the p21-saRNA-322. The expression of P21 protein and p21 mRNA were measured using the Western blot and reverse transcriptase polymerase chain reaction (RT-PCR). The effect of p21-saRNA-322 on cancer cells was evaluated in vitro; and furthermore, a xenograft colorectal tumor mode in mice was established to estimate the tumor suppressing ability of p21-saRNA-322 in vivo. The results showed that in all three colorectal cancer cell lines, the expression of p21 mRNA and P21 protein were dramatically elevated after p21-saRNA-322 transfection. Transfection of p21-saRNA-322 caused apoptosis and cell cycle arrest at the G0/G1. Furthermore, anti-proliferation effect, reduction of colonies formation and cell senescence were observed in p21-saRNA-322 treated cells. Animal studies showed that p21-saRNA-322 treatment significantly inhibited the HT-29 tumor growth and facilitated p21 activation in vivo. These results indicated that, p21-saRNA-322-induceded up-regulation of p21 might be a promising therapeutic option for the treatment of colorectal cancer.

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“…A number of studies have focused on the relationship between PADI4 and tumor suppressor p53, a sequence-specific transcription factor. p53 is activated upon many cellular stresses and responds to these stress events via regulating cell cycle progression, apoptosis, DNA repair, senescence, cellular metabolism, or autophagy [42,43]. PADI4 can bind to the C-terminus of p53 and is involved in the repression of p53 transcriptional activity, which suggests that PADI4 is a co-repressor of p53.…”

Section: Padi4 and Tumor Developmentmentioning

confidence: 99%

Role of citrullination modification catalyzed by peptidylarginine deiminase 4 in gene transcriptional regulation

Zhai¹,

Wang²,

Zhao³

et al. 2017

ABBS

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Peptidylarginine deiminase 4 (PADI4), a new histone modification enzyme, which converts both arginine and monomethyl-arginine to citrulline, has gained massive attention in recent years as a potential regulator of gene transcription. Recent studies have shown that arginine residues R2, R8, R17, and R26 in the H3 tail and R3 in the H4 tail can be deiminated by PADI4. This kind of histone post-translational modification has the potential to antagonize histone methylation and coordinate with histone deacetylation to regulate gene transcription. PADI4 also deiminates non-histone proteins, such as p300, NPM1, ING4, RPS2, and DNMT3A. PADI4 has been shown to involve in cell apoptosis and differentiation. Moreover, PADI4 can interact with tumor suppressor p53 and regulate the transcriptional activity of p53. Dysregulation of PADI4 is implicated in a variety of diseases, including rheumatoid arthritis, tumor development, and multiple sclerosis. A wide variety of PADI4 inhibitors have been identified. Further understanding of PADI4 functions may lead to novel diagnostic and therapeutic approaches in these diseases. This review summarizes the recent progress in the study of the regulation mechanism of PADI4 on gene transcription and the major physiological functions of PADI4 in human diseases.

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The impact of R213 mutation on p53-mediated p21 activity

Cited by 21 publications

References 18 publications

Molecular mechanism leading to SAHA-induced autophagy in tumor cells: evidence for a p53-dependent pathway

Molecular mechanism leading to SAHA-induced autophagy in tumor cells: evidence for a p53-dependent pathway

Specific up-regulation of p21 by a small active RNA sequence suppresses human colorectal cancer growth

Role of citrullination modification catalyzed by peptidylarginine deiminase 4 in gene transcriptional regulation

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