INTERACTION BETWEEN RB PROTEIN AND HMG1/2

RB 蛋白和 HMG1/2 之间的相互作用

• 批准号: 6522543
• 负责人: ANTON CHESTUKHIN
• 金额: $ 5.01万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6522543
• 关键词: Baculoviridae; Insecta; SDS polyacrylamide gel electrophoresis; affinity chromatography; autoradiography; chimeric proteins; gene induction /repression; genetic promoter element; glutathione transferase; immunoprecipitation; intermolecular interaction; luciferin monooxygenase; nonhistone nucleoprotein; plasmids; reporter genes; retinoblastoma protein; transcription factor; transfection /expression vector

The of retinoblastoma susceptibility gene product (pRb) is a potent tumor supressor that is frequently mutated in numerous malignancies including leukemias. pRb and related proteins, p107 and p130 binds to and inactivates different members of the E2F family of transcription factors. In addition to E2F pRb can interact with other factors that modulate transcriptional activity of the pRb-E2F complexes such as: HBP1 (HMG-box- containing transcriptional repressor), hBRGl and hBRM (mammalian homologues of SNF2/SWI2 yeast transcription activator), and histone deacetylase (the enzyme involved in chromatin structure rearrangement) have all been reported to interact with pRb and to modulate its transcriptional activity. Binding of each of these modulators to pRb occur in an LXCXE motif-dependent manner. The LXCXE motif was originally found in certain viral oncoproteins (SV40 T antigen, HPV-16 E7, adenoviral E1A) that also are known to bind to pRb. Preliminary results from our laboratory raised a possibility that pRb may also interact with the HMG1/2 class of proteins. The HMG proteins are nuclear, non-histone structural elements of chromatin that contain an LXCXE motif. We propose to investigate whether the HMG class of proteins contributes to the pRb-dependent regulation of transcription. To address this question we will study specific association of HMG2 and pRB in vitro and in vivo model systems. To investigate the functional significance of HMG2/pRb interaction we will examine effect of HMG on pRb ability to repress transcription in model assays.

视网膜母细胞瘤易感基因产物（pRb）是一种有效的肿瘤抑制因子，在包括白血病在内的多种恶性肿瘤中经常发生突变。 pRb 和相关蛋白、p107 和 p130 与 E2F 转录因子家族的不同成员结合并使其失活。 除了E2F之外，pRb还可以与调节pRb-E2F复合物的转录活性的其他因子相互作用，例如：HBP1（含有HMG盒的转录阻遏物）、hBRG1和hBRM（SNF2/SWI2酵母转录激活物的哺乳动物同源物），以及据报道，组蛋白脱乙酰酶（参与染色质结构重排的酶）可与 pRb 相互作用并调节其转录活性。 这些调节剂与 pRb 的结合以 LXCXE 基序依赖性方式发生。 LXCXE 基序最初发现于某些病毒癌蛋白（SV40 T 抗原、HPV-16 E7、腺病毒 E1A）中，已知这些蛋白也与 pRb 结合。 我们实验室的初步结果提出了 pRb 也可能与 HMG1/2 类蛋白质相互作用的可能性。 HMG 蛋白是染色质的核非组蛋白结构元件，包含 LXCXE 基序。我们建议研究 HMG 类蛋白质是否有助于 pRb 依赖性转录调节。 为了解决这个问题，我们将在体外和体内模型系统中研究 HMG2 和 pRB 的特定关联。 为了研究 HMG2/pRb 相互作用的功能意义，我们将在模型测定中检查 HMG 对 pRb 抑制转录能力的影响。