Rbm24, an RNA-binding Protein and a Target of p53, Regulates p21 Expression via mRNA Stability

被引:55
作者
Jiang, Yuqian [1 ]
Zhang, Min [1 ]
Qian, Yingjuan [1 ]
Xu, Enshun [1 ]
Zhang, Jin [1 ]
Chen, Xinbin [1 ]
机构
[1] Univ Calif Davis, Comparat Oncol Lab, Davis, CA 95616 USA
基金
美国国家卫生研究院;
关键词
Cancer Biology; Cell Cycle; mRNA Decay; p53; RNA-binding Protein; CELL-CYCLE; RNPC1; GENE; PATHWAYS; ARREST; IDENTIFICATION; STABILIZATION; WAF1/CIP1; RADIATION; MEDIATOR;
D O I
10.1074/jbc.M113.524413
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Post-transcriptional regulation of p21 expression is still not fully understood. Results: Rbm24 is induced by p53 and serves as a mediator of p53 to regulate p21 expression via binding to its 3-UTR. Conclusion: Rbm24, an RNA-binding protein and a target of p53, enhances p21 expression via mRNA stability. Significance: A novel p53 target gene Rbm24 is identified to regulate p21 mRNA stability. p21, a cyclin-dependent kinase inhibitor, is necessary for proper control of the cell cycle and premature senescence. Thus, p21 expression needs to be tightly controlled. In this study, we found that Rbm24, an RNA-binding protein and a target gene of the p53 protein, can regulate p21 expression via mRNA stability. Specifically, we showed that Rbm24 is induced by DNA damage and Mdm2 inhibitor Nutlin-3. We also found that p53 protein binds to and activates the promoter of the Rbm24 gene. Moreover, we found that overexpression of Rbm24 increases, whereas knockdown of Rbm24 decreases, p21 mRNA and protein expression. In addition, we demonstrated that overexpression of Rbm24 enhances the half-life of p21 transcript. Consistent with this, we provided evidence that Rbm24 binds to the 3-untranslated region (3-UTR) of p21 transcript and an AU/U-rich element in the p21 3-UTR is necessary for Rbm24 to increase p21 expression. Finally, we showed that the RNA recognition motif in Rbm24 is required for binding to p21 transcript and subsequently for inducing p21 expression. Altogether, we uncovered that Rbm24 is a novel player in the p53 pathway, which may be explored to restore proper cell cycle control in p53-deficient tumors via p21.
引用
收藏
页码:3164 / 3175
页数:12
相关论文
共 42 条
[1]   Requirement for p53 and p21 to sustain G2 arrest after DNA damage [J].
Bunz, F ;
Dutriaux, A ;
Lengauer, C ;
Waldman, T ;
Zhou, S ;
Brown, JP ;
Sedivy, JM ;
Kinzler, KW ;
Vogelstein, B .
SCIENCE, 1998, 282 (5393) :1497-1501
[2]   Multiple putative oncogenes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression [J].
Carvalho, B. ;
Postma, C. ;
Mongera, S. ;
Hopmans, E. ;
Diskin, S. ;
van de Wiel, M. A. ;
van Criekinge, W. ;
Thas, O. ;
Matthaei, A. ;
Cuesta, M. A. ;
Droste, J. S. Terhaar sive ;
Craanen, M. ;
Schroeck, E. ;
Ylstra, B. ;
Meijer, G. A. .
GUT, 2009, 58 (01) :79-89
[3]  
CHEN XB, 1995, CANCER RES, V55, P4257
[4]   Serine 123 Phosphorylation Modulates p21 Protein Stability and Activity by Suppressing Ubiquitin-independent Proteasomal Degradation [J].
Chen, Xiangling ;
Zhang, Jin ;
Zhang, Min ;
Liu, Shou ;
Yan, Wensheng ;
Jung, JinHyuk ;
Chen, Xinbin .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (41) :34410-34418
[5]   RNPC1 modulates the RNA-binding activity of, and cooperates with, HuR to regulate p21 mRNA stability [J].
Cho, Seong Jun ;
Zhang, Jin ;
Chen, Xinbin .
NUCLEIC ACIDS RESEARCH, 2010, 38 (07) :2256-2267
[6]   RNA recognition motifs:: boring?: Not quite [J].
Clery, Antoine ;
Blatter, Markus ;
Allain, Frederic H-T .
CURRENT OPINION IN STRUCTURAL BIOLOGY, 2008, 18 (03) :290-298
[7]   Translational inhibition in vitro of human papillomavirus type 16 L2 mRNA mediated through interaction with heterogenous ribonucleoprotein K and Poly(rC)-binding proteins 1 and 2 [J].
Collier, B ;
Goobar-Larsson, L ;
Sokolowski, M ;
Schwartz, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (35) :22648-22656
[8]   The cell cycle and cancer [J].
Collins, K ;
Jacks, T ;
Pavletich, NP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (07) :2776-2778
[9]  
Dohn Michael, 2003, Methods Mol Biol, V223, P221
[10]   ALTERED REGULATION OF G(1)-CYCLINS IN SENESCENT HUMAN-DIPLOID FIBROBLASTS - ACCUMULATION OF INACTIVE CYCLIN-E-CDK2 AND CYCLIN-D1-CDK2 COMPLEXES [J].
DULIC, V ;
DRULLINGER, LF ;
LEES, E ;
REED, SI ;
STEIN, GH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (23) :11034-11038