Signal Transduction by the Retinoblastoma Protein

视网膜母细胞瘤蛋白的信号转导

• 批准号: 6913537
• 负责人: WILLIAM G. KAELIN
• 金额: $ 30.78万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6913537
• 关键词: biological signal transduction; cell cycle proteins; cell differentiation; cell line; cyclin dependent kinase; cyclins; enzyme complex; enzyme substrate; genetic promoter element; genetic transcription; laboratory mouse; mutant; phosphorylation; protein protein interaction; protein sequence; protein structure function; retinoblastoma protein; tissue /cell culture; transcription factor; tumor suppressor proteins

DESCRIPTION (provided by applicant): Cancer cells exhibit abnormalities in cell-cycle control and in differentiation. This is due, at least partly, to the fact that most cancer cells harbor mutations that compromise the function of the retinoblastoma protein (pRB.) The best understood targets of pRB are members of the E2F cell-cycle regulatory transcription factor family. E2F, unfettered by pRB, can induce cellular proliferation but can also induce apoptosis. E2F is neutralized in S-phase by cyclin NCdk2. Short peptides ('RXL peptides') that block the interaction of cyclin A/cdk2 with E2F selectively kill transformed cells, perhaps due to the high levels of E2F that typify cancer cells compared to normal cells. Specific aim 1 will be to confirm or refute the hypothesis that RXL peptides kill cells by preventing the neutralization of E2F by cyclin A/cdk2. Control of the G1/S transition by pRB is linked to its ability to repress E2F-responsive promoters, whereas control of differentiation is not. Two additional pRB interactors, EID1 and RBP2, might be linked to differentiation control. EID1 inhibits p300/CBP histone acetylase activity, blocks differentiation, and is rapidly polyubiquitinated as cell exit the cell-cycle. Understanding the control of EID1 turnover will be the focus of Specific aim 2. Preliminary data suggests a role of pRB and RBP2 in differentiation-dependent chromatin remodeling. The functional significance of pRB/RBP2 interactions will be addressed in Specific aim 3 and specific aim 4 will ask whether EID1 and/or RBP2 contribute to the developmental abnormalities observed in RB-/- mice.

描述（由申请人提供）：癌细胞在细胞周期控制和分化中表现出异常。这至少部分是由于大多数癌细胞含有损害视网膜母细胞瘤蛋白（pRB）功能的突变。pRB的最佳靶点是E2 F细胞周期调节转录因子家族的成员。E2 F不受pRB的限制，可以诱导细胞增殖，但也可以诱导细胞凋亡。E2 F在S期被细胞周期蛋白NCdk 2中和。阻断细胞周期蛋白A/cdk 2与E2 F相互作用的短肽（“RXL肽”）选择性地杀死转化细胞，这可能是由于与正常细胞相比，癌细胞典型的E2 F水平高。具体目标1将是证实或反驳RXL肽通过阻止细胞周期蛋白A/cdk 2中和E2 F来杀死细胞的假设。pRB对G1/S转换的控制与其抑制E2 F应答启动子的能力有关，而对分化的控制则与此无关。两个额外的pRB相互作用，EID 1和RBP 2，可能与分化控制。EID 1抑制p300/CBP组蛋白乙酰化酶活性，阻断分化，并在细胞退出细胞周期时快速聚泛素化。理解EID 1周转的控制将是具体目标2的重点。初步数据表明pRB和RBP 2在分化依赖性染色质重塑中的作用。pRB/RBP 2相互作用的功能意义将在具体目标3中阐述，具体目标4将询问EID 1和/或RBP 2是否有助于在RB-/-小鼠中观察到的发育异常。