DNA damage triggers the nuclear accumulation of RASSF6 tumor suppressor protein via CDK9 and BAF53 to regulate p53-target gene transcription

2021 ◽  
Author(s):  
Joshua Agbemefa Kuleape ◽  
Shakhawoat Hossain ◽  
Caleb Kwame Sinclear ◽  
Takanobu Shimizu ◽  
Hiroaki Iwasa ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Gene Transcription ◽  
Nuclear Export ◽  
Target Gene ◽  
Nuclear Accumulation ◽  
P53 Expression ◽  
Cycle Arrest ◽  
P53 Target Gene ◽  
Target Gene Transcription

RASSF6, a member of the tumor suppressor Ras-association domain family (RASSF) proteins, regulates cell cycle arrest and apoptosis via p53 and plays a tumor suppressor role. We previously reported that RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. In this study, we demonstrated that RASSF6 has nuclear-localization and nuclear-export signals and that DNA damage triggers the nuclear accumulation of RASSF6. We found that RASSF6 directly binds to BAF53, the component of SWI/SNF complex. DNA damage induces CDK9-mediated phosphorylation of BAF53, which enhances the interaction with RASSF6 and increases the amount of RASSF6 in the nucleus. Subsequently, RASSF6 augments the interaction between BAF53 and BAF60a, another component of SWI/SNF complex, and further promotes the interaction of BAF53 and BAF60a with p53. BAF53 silencing or BAF60a silencing attenuates RASSF6-mediated p53-target gene transcription and apoptosis. Thus, RASSF6 is involved in the regulation of DNA damage-induced complex formation including CDK9, BAF53, BAF60a, and p53.

scholarly journals Impaired p53 Expression, Function, and Nuclear Localization in Calreticulin-deficient Cells

2004 ◽  
Vol 15 (4) ◽  
pp. 1862-1870 ◽  
Author(s):  
Nasrin Mesaeli ◽  
Clark Phillipson
Keyword(s):  
Dna Damage ◽  
Binding Site ◽  
Nuclear Localization ◽  
P53 Protein ◽  
Nuclear Accumulation ◽  
P53 Expression ◽  
Cycle Arrest ◽  
Expression Of Genes ◽  
The Stability

The tumor suppressor protein, p53 is a transcription factor that not only activates expression of genes containing the p53 binding site but also can repress the expression of some genes lacking this binding site. Previous studies have shown that overexpression of wild-type p53 leads to apoptosis and cell cycle arrest. DNA damage, such as that caused by UV irradiation, results in p53 stabilization and nuclear localization that subsequently induces apoptosis. Recently, the level of calreticulin (CRT) has been correlated with the rate of apoptosis. Therefore, the aim of this study was to investigate the role of CRT in the regulation of apoptosis via modulating p53 function and expression. Here we show a significant decrease in both basal and DNA damage induced p53 functions in the CRT-deficient cells (crt-/-). This study is the first to demonstrate that CRT function is required for the stability and localization of the p53 protein. By using immuonocytochemical techniques, we showed that observed changes in p53 in the crt-/- cells are due to the nuclear accumulation of Mdm2 (murine double minute gene). These results, lead us to conclude that CRT regulates p53 function by affecting its rate of degradation and nuclear localization.

Human Metalloproteinase-1 (Collagenase-1) Is a Tumor Suppressor Protein p53 Target Gene

1999 ◽  
Vol 878 (1 INHIBITION OF) ◽  
pp. 638-641 ◽  
Author(s):  
YUBO SUN ◽  
YI SUN ◽  
LEONOR WENGER ◽  
JONI L. RUTTER ◽  
CONSTANCE E. BRINCKERHOFF ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Target Gene ◽  
Tumor Suppressor Protein ◽  
Tumor Suppressor Protein P53 ◽  
Protein P53 ◽  
P53 Target Gene

scholarly journals Specific expression of the Fusarium transposon Fot1 and effects on target gene transcription

1999 ◽  
Vol 31 (5) ◽  
pp. 1373-1383 ◽  
Author(s):  
Francine Deschamps ◽  
Thierry Langin ◽  
Patricia Maurer ◽  
Catherine Gerlinger ◽  
Beatrice Felenbok ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Target Gene ◽  
Specific Expression ◽  
Target Gene Transcription

scholarly journals The RASSF6 Tumor Suppressor Protein Regulates Apoptosis and Cell Cycle Progression via Retinoblastoma Protein

2018 ◽  
Vol 38 (17) ◽  
Author(s):  
Shakhawoat Hossain ◽  
Hiroaki Iwasa ◽  
Aradhan Sarkar ◽  
Junichi Maruyama ◽  
Kyoko Arimoto-Matsuzaki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Loss Of Function ◽  
Cycle Progression ◽  
P53 Expression ◽  
Cycle Arrest ◽  
Hct116 Cells

ABSTRACT RASSF6 is a member of the tumor suppressor Ras association domain family (RASSF) proteins. RASSF6 is frequently suppressed in human cancers, and its low expression level is associated with poor prognosis. RASSF6 regulates cell cycle arrest and apoptosis and plays a tumor suppressor role. Mechanistically, RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. However, RASSF6 also induces cell cycle arrest and apoptosis in a p53-negative background, which implies that the tumor suppressor function of RASSF6 does not depend solely on p53. In this study, we revealed that RASSF6 mediates cell cycle arrest and apoptosis via pRb. RASSF6 enhances the interaction between pRb and protein phosphatase. RASSF6 also enhances P16INK4A and P14ARF expression by suppressing BMI1. In this way, RASSF6 increases unphosphorylated pRb and augments the interaction between pRb and E2F1. Moreover, RASSF6 induces TP73 target genes via pRb and E2F1 in a p53-negative background. Finally, we confirmed that RASSF6 depletion induces polyploid cells in p53-negative HCT116 cells. In conclusion, RASSF6 behaves as a tumor suppressor in cancers with loss of function of p53, and pRb is implicated in this function of RASSF6.

scholarly journals Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4

2008 ◽  
Vol 28 (15) ◽  
pp. 4745-4758 ◽  
Author(s):  
Pingxin Li ◽  
Hongjie Yao ◽  
Zhiqiang Zhang ◽  
Ming Li ◽  
Yuan Luo ◽  
...  
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Peptidylarginine Deiminase ◽  
Uv Treatment ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Cycle Arrest ◽  
P53 Target Gene ◽  
P53 Target Genes ◽  
P21 Promoter

ABSTRACT Histone Arg methylation has been correlated with transcriptional activation of p53 target genes. However, whether this modification is reversed to repress the expression of p53 target genes is unclear. Here, we report that peptidylarginine deiminase 4, a histone citrullination enzyme, is involved in the repression of p53 target genes. Inhibition or depletion of PAD4 elevated the expression of a subset of p53 target genes, including p21/CIP1/WAF1, leading to cell cycle arrest and apoptosis. Moreover, the induction of p21, cell cycle arrest, and apoptosis by PAD4 depletion is p53 dependent. Protein-protein interaction studies showed an interaction between p53 and PAD4. Chromatin immunoprecipitation assays showed that PAD4 is recruited to the p21 promoter in a p53-dependent manner. RNA polymerase II (Pol II) activities and the association of PAD4 are dynamically regulated at the p21 promoter during UV irradiation. Paused RNA Pol II and high levels of PAD4 were detected before UV treatment. At early time points after UV treatment, an increase of histone Arg methylation and a decrease of citrullination were correlated with a transient activation of p21. At later times after UV irradiation, a loss of RNA Pol II and an increase of PAD4 were detected at the p21 promoter. The dynamics of RNA Pol II activities after UV treatment were further corroborated by permanganate footprinting. Together, these results suggest a role of PAD4 in the regulation of p53 target gene expression.

PS18 - 87. A novel FPLD-associated PPARgamma mutant (E379K) displays a selective defect in target gene transcription

2012 ◽  
Vol 10 (3) ◽  
pp. 161-161
Author(s):  
Arjen Koppen ◽  
David Cassiman ◽  
Mariette Kranendonk ◽  
Marian Groot Koerkamp ◽  
Nicole Hamers ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Target Gene ◽  
Target Gene Transcription
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