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.

p53的突变发生在所有肿瘤中的50％以上，包括结肠，乳腺癌和肺部。肿瘤 表达升高的突变体p53水平可能与p53-null癌症的预后更差有关。 该研究计划的长期目标继续关注突变体的机制 p53有助于肿瘤发生。突变p53增强了p53阴性细胞系的致瘤潜力 长期以来，这种活动已被认为与其有选择性反式激活人类的能力有关 多药电阻（MDR1）启动子。我们先前确定突变体p53调节内源性 MDR1和C-MYC基因表达，并且该活性需要完整的C末端。在以前的资金中 我们确定了该域中的关键赖氨酸，通常在野生型p53中被乙酰化 突变体p53转移所需的细胞应激。最重要的是，但自相矛盾的是，我们 证明该区域对于突变体p53促进肿瘤性是不可使用的。这些结果脱节了 在考虑突变体p53增益模型中，从肿瘤性重新激活并代表了范式转移 功能。相反，我们的数据支持一种机制，突变体p53结合并稳定MDM2 proto- 癌基因蛋白可能导致非整倍性，增生和最终导致肿瘤细胞生长。持续的 通过这种推理，我们生成了缺少p19 ARF，MDM2和P53的三重基因敲除小鼠模型。老鼠 源自这些小鼠的胚胎成纤维细胞（MEF）不是肿瘤的，但值得注意的是双敲除 MEF缺乏p53和ARF很容易在裸鼠中形成肿瘤。这些结果表明MDM2可能是 肿瘤细胞生长所必需的。本研究中提出的实验旨在检验此假设 通过解决以下特定问题，使用基于细胞和动物的方法：1）MDM2 与突变p53合作在肿瘤性上？ 2）MDM2对突变体P53的体内贡献是什么 功能增益？ 3）翻译后修饰会影响突变体p53功能的增益吗？我们的 研究结果表明，野生型和突变体p53的结构要求有显着差异 功能，这可能为开发治疗癌症的治疗方法提供可剥削的基础。

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

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

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