p12CDK2-AP1 in Cell Cycle Control & Oral Carcinogenesis

p12CDK2-AP1 在细胞周期控制中的作用

• 批准号: 6816786
• 负责人: David T Wong
• 金额: $ 5.61万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6816786
• 关键词: p12CDK2; AP1; Cell; Cycle; Control

DESCRIPTION (provided by applicant): Clinical correlation, in vitro and in rive studies strongly suggest that deregulation of cell cycle progression can result in proliferative disorders including cancer. Cellular proliferation is regulated by mitogenic stimuli and negative growth regulators, while anti-proliferative signals serve to gate the proliferative response to mitogens. The long-term goal of these studies is to gain insight into the role of p12 cD_-Apl, known to be a growth suppressor, in cell-cycle regulation, as well as normal and oral cancer development. Understanding its mechanism of action in cell-cycle control via its association with cyclin-dependent kinases-2 (CDK2) may have clinical applications in the prevention and treatment of cancer. Re-expression ofp12 cD_-Am in oral cancer cells in vitro is associated with reversion of transformation phenotypes, as indicated by morphological, doubling time and density-dependent growth studies. Recent data further tiesp12 CDK2-Apl to the TGF- [31 anti-proliferative pathway as a potential negative CDK2 regulator in TGF-131-mediated pRB hypophosphorylation. The Aims of this application include characterizing the in vivo role ofp12 cDm-Aplas a negative regulator of CDK2 activities and determining how this interaction is involved in the TGF- [31-antiproliferative pathway. With the long-range objective of future clinical applications, Specific Aims include 1) identification of the cis and trans elements responsible for the TGF-131 induction of the p12 gene, 2) examination of the molecular details of p12 cDm-Am in the anti-proliferative effect and 3) validation of in vitro results by examining the expression profiles of p12 cDm-Am, CDK2, TGF- [31 signaling components and pRB in normal and cancer oral epithelia in vivo.

描述（由申请人提供）：临床相关性，体外和内部研究强烈表明，细胞周期进程的失调可导致包括癌症在内的增殖性疾病。细胞增殖受有丝分裂刺激和负生长调节剂的调节，而抗增殖信号则用于限制对有丝分裂原的增殖反应。这些研究的长期目标是深入了解p12 cd_apl（已知是一种生长抑制因子）在细胞周期调节以及正常和口腔癌发展中的作用。通过其与细胞周期蛋白依赖性激酶-2 （CDK2）的关联来了解其在细胞周期控制中的作用机制，可能在癌症的预防和治疗中具有临床应用价值。形态学、倍增时间和密度依赖性生长研究表明，体外口腔癌细胞中p12 - cd_am的重新表达与转化表型的逆转有关。最近的数据进一步将esp12 CDK2- apl与TGF-[31]抗增殖途径联系起来，在TGF-131介导的pRB低磷酸化中作为潜在的CDK2负调控因子。本应用的目的包括表征CDK2活性的负调节因子p12 - cDm-Aplas在体内的作用，并确定这种相互作用如何参与TGF-[31-抗增殖途径。针对未来临床应用的长远目标，具体目标包括：1)鉴定TGF-131诱导p12基因的顺式和反式元件；2)检测p12 cDm-Am抗增殖作用的分子细节；3)通过检测p12 cDm-Am、CDK2、TGF-[31]信号成分和pRB在体内正常和肿瘤口腔上皮中的表达谱，验证体外结果。