Mutant p53 Gain of Function in Tumorigenesis

突变体 p53 在肿瘤发生中获得功能

• 批准号: 7172975
• 负责人: GERARD PAUL ZAMBETTI
• 金额: $ 30.08万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172975
• 关键词: ABCB1 gene; Accounting; Acetylation; Acute T Cell Leukemia; Address; Affect; Alanine; Amino Acids; Aneuploidy; Animals; Applications Grants; Arginine; Binding; Biological Assay; Breast; C-terminal; Carcinoma; Cell Line; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cellular Stress; Charge; Codon Nucleotides; Colon; Condition; DNA Binding; Data; Development; Disease; Disruption; EP300 gene; Ectopic Expression; Embryo; Event; Fibroblasts; Frequencies; Funding; Gene Expression; Genus Cola; Goals; Growth; Histidine; Human; Hyperplasia; Implant; Infection; Knock-out; Knockout Mice; Lead; Link; Liver; Localized; Lung; Lysine; MDM2 gene; MDM2 gene; Malignant Neoplasms; Metastatic to; Missense Mutation; Modeling; Modification; Multi-Drug Resistance; Mus; Mutant Strains Mice; Mutation; Neoplasm Metastasis; Nuclear; Nucleotides; Nude Mice; Null Lymphocytes; Numbers; Oncogenes; Oncogenic; Phosphorylation; Play; Post-Translational Protein Processing; Predisposition; Property; Protein Binding; Protein p53; Proteins; Proto-Oncogene Proteins; RNA Splicing; Regulation; Reporter; Research; Research Design; Research Personnel; Retroviridae; Role; SCID Mice; Series; Site; Stress; TP53 gene; Testing; Therapeutic; Transactivation; Transfection; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-Derived; Tumorigenicity; Variant; base; c-myc Genes; cell growth; cell type; clinically relevant; design; gain of function; in vivo; leukemia/lymphoma; loss of function; mouse model; mutant; neoplastic cell; outcome forecast; p53-binding protein; programs; promoter; reconstitution; research study; response; sarcoma; stable cell line; tumor; tumor growth; tumorigenesis; tumorigenic

Mutation of p53 occurs in more than 50% of all tumors, including those of colon, breast and lung. Tumors expressing elevated levels of mutant p53 may be associated with a worse prognosis than p53-null cancers. The long.term goal of this research program continues to focus on the mechanisms by which mutant p53 contributes to tumorigenesis. Mutant p53 enhances the tumorigenic potential of p53-negative cell lines and this activity has long been considered to be linked to its ability to selectively transactivate the human multi-drug resistance (MDR1) promoter. We previously established that mutant p53 regulates endogenous MDR1 and c-myc gene expression and that this activity requires an intact C-terminus. In the previous funding period we identified key lysines in this domain, which normally become acetylated in wild-type p53 during cell stress, that are required for mutant p53-transactivation. Most importantly but paradoxically, we demonstrated that this region is dispensable for mutant p53 to promote tumorigenicity. These results uncouple transactivation from tumorigenicity and represent a paradigm shift in considering models for mutant p53 gain of function. Rather, our data support a mechanism by which mutant p53 binds and stabilizes the Mdm2 proto- oncogene protein, which could lead to aneuploidy, hyperplasia and ultimately tumor cell growth. Consistent with this reasoning, we generated a triple knockout mouse model that lacks p19 ARF,Mdm2 and p53. Mouse embryo fibroblasts (MEFs) derived from these mice are not tumorigenic, but remarkably, double knockout MEFs lacking both p53 and ARF readily form tumors in nude mice. These results suggest that Mdm2 may be required for tumor cell growth. The experiments proposed in this study are designed to test this hypothesis using cell and animal based approaches by addressing the following specific questions: 1) Does Mdm2 cooperate with mutant p53 in tumorigenicity?; 2) What is the in vivo contribution of Mdm2 to mutant p53 gain of function?; and 3) Do post-translational modifications influence mutant p53 gain of function? Our findings demonstrate significant differences in the structural requirements for wild-type and mutant p53 function, which may provide an exploitable basis for developing therapeutic approaches to treating cancer.

超过50%的肿瘤发生p53突变，包括结肠癌、乳腺癌和肺癌。肿瘤

项目成果

Gene expression profiling of childhood adrenocortical tumors.

• DOI: 10.1158/0008-5472.can-06-3767
• 发表时间: 2007-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: A. West;G. Neale;S. Pounds;Bonald C Figueredo;C. Rodriguez Galindo;M. Pianovski;A. O. Oliveira Filho;D. Malkin;E. Lalli;R. Ribeiro;G. Zambetti

Towards an understanding of the role of p53 in adrenocortical carcinogenesis.

• DOI: 10.1016/j.mce.2011.09.010
• 发表时间: 2012-03-31
• 期刊: MOLECULAR AND CELLULAR ENDOCRINOLOGY
• 影响因子: 4.1
• 作者: Wasserman, Jonathan D.;Zambetti, Gerard P.;Malkin, David
• 通讯作者: Malkin, David

Cytokine rescue of p53-dependent apoptosis and cell cycle arrest is mediated by distinct Jak kinase signaling pathways.

• DOI: 10.1101/gad.12.8.1099
• 发表时间: 1998-04
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Frederick W. Quelle;Jinling Wang;Jian Feng;Demin Wang;John L. Cleveland;J. N. Ihle;Gerard P. Zambetti

Identification of a novel TP53 germline mutation E285V in a rare case of paediatric adrenocortical carcinoma and choroid plexus carcinoma.

• DOI: 10.1136/jmg.2008.059568
• 发表时间: 2008-09
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Russell-Swetek A;West AN;Mintern JE;Jenkins J;Rodriguez-Galindo C;Ribeiro R;Zambetti GP
• 通讯作者: Zambetti GP

High frequency of loss of heterozygosity at 11p15 and IGF2 overexpression are not related to clinical outcome in childhood adrenocortical tumors positive for the R337H TP53 mutation.

11p15 杂合性丢失的高频率和 IGF2 过表达与 R337H TP53 突变呈阳性的儿童肾上腺皮质肿瘤的临床结果无关。

• DOI: 10.1016/j.cancergencyto.2008.05.010
• 发表时间: 2008
• 期刊: Cancer genetics and cytogenetics
• 作者: Rosati,Roberto;Cerrato,Flavia;Doghman,Mabrouka;Pianovski,MaraAD;Parise,GuilhermeA;Custódio,Gislaine;Zambetti,GerardP;Ribeiro,RaulC;Riccio,Andrea;Figueiredo,BonaldC;Lalli,Enzo
• 通讯作者: Lalli,Enzo