As a transcription factor, p53 exerts a tumor suppressor activity by regulating a diverse array of genes involved in the control of cell cycle, apoptosis, differentiation, and DNA repair. Since the last competitive review of this project, we have identified seven novel p53 target genes. For example, we have found that MCGIO can induce cell cycle arrest and apoptosis and TAP1 may mediate tumor surveillance. We have also found that p2lB, a variant of p2l WAF1, is expressed in the Golgi apparatus and can induce apoptosis. These results have led us to hypothesize that multiple, parallel cell cycle control and apoptotic pathways are involved in p53 tumor suppression. To explore these further, we propose: (1) To identify additional novel p53 target genes. We will use the Affymetrix GeneChip assay to identify additional p53 target genes involved in the control of the cell cycle and apoptosis. We will analyze patterns of gene expression in response to various levels of p53 activation. Furthermore, we will determine whether one or more p53 response elements are present in the promoter or introns of the induced genes, and whether p53 regulates, or binds to, the potential response element(s). (2) To determine the mechanism by which wild type p53 and various mutants differentially regulate gene expression. (3) To determine the role of p2lB and MCG1O in p53 tumor suppression. We will analyze the role of p21B in p53-dependent apoptosis by somatic gene targeting and the mechanism by which p21 B induces apoptosis from within the Golgi. We will also determine the role of MCG1O in p53 tumor suppression, the mechanism by which MCG1O regulates gene expression, and whether MCG10 mediates activation or repression of some p53 target genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076069-09
Application #
6798802
Study Section
Radiation Study Section (RAD)
Program Officer
Blair, Donald G
Project Start
1997-12-05
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
9
Fiscal Year
2004
Total Cost
$290,363
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Zhang, Jin; Xu, Enshun; Ren, Cong et al. (2018) Genetic Ablation of Rbm38 Promotes Lymphomagenesis in the Context of Mutant p53 by Downregulating PTEN. Cancer Res 78:1511-1521
Zhang, Jin; Chen, Xinbin (2018) p53 tumor suppressor and iron homeostasis. FEBS J :
Zhang, Min; Zhang, Yanhong; Xu, Enshun et al. (2018) Rbm24, a target of p53, is necessary for proper expression of p53 and heart development. Cell Death Differ 25:1118-1130
Zhang, Yanhong; Qian, Yingjuan; Zhang, Jin et al. (2017) Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. Genes Dev 31:1243-1256
Yang, Hee Jung; Zhang, Jin; Yan, Wensheng et al. (2017) Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner. Proc Natl Acad Sci U S A 114:11500-11505
Zhang, Jin; Lucchesi, Christopher; Chen, Xinbin (2016) A new function for p53 tetramerization domain in cell fate control. Cell Cycle 15:2854-2855
Wang, Junjian; Wang, Haibin; Wang, Ling-Yu et al. (2016) Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy. Cell Death Differ 23:1886-1896
Lucchesi, Chris; Zhang, Jin; Chen, Xinbin (2016) Modulation of the p53 family network by RNA-binding proteins. Transl Cancer Res 5:676-684
Yan, Wensheng; Scoumanne, Ariane; Jung, Yong-Sam et al. (2016) Mice deficient in poly(C)-binding protein 4 are susceptible to spontaneous tumors through increased expression of ZFP871 that targets p53 for degradation. Genes Dev 30:522-34
Zhang, Min; Zhang, Jin; Yan, Wensheng et al. (2016) p73 expression is regulated by ribosomal protein RPL26 through mRNA translation and protein stability. Oncotarget 7:78255-78268

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