INTERACTION BETWEEN RB PROTEIN AND HMG1/2

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许多恶性肿瘤中经常发生突变。 pRb和相关蛋白p107和p130结合并灭活转录因子E2 F家族的不同成员。 除了E2 F之外，pRb还可以与调节pRb-E2 F复合物的转录活性的其他因子相互作用，例如HBP 1（含HMG盒的转录阻遏物）、hBRG 1和hBRM（SNF 2/SWI 2酵母转录激活因子的哺乳动物同源物）以及组蛋白脱乙酰酶（参与染色质结构重排的酶）都已被报道与pRb相互作用并调节其转录活性。 这些调节剂中的每一种与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（SV 40 T抗原、HPV-16 E7、腺病毒E1 A）中，已知它们也与pRb结合。 我们实验室的初步结果提出了一种可能性，即pRb也可能与HMG 1/2类蛋白相互作用。 HMG蛋白是染色质的核非组蛋白结构元件，其含有LXCXE基序。我们建议调查是否HMG类蛋白质有助于pRb依赖的转录调控。 为了解决这个问题，我们将在体外和体内模型系统中研究HMG 2和pRB的特异性关联。 为了研究HMG 2/pRb相互作用的功能意义，我们将在模型测定中检测HMG对pRb抑制转录能力的影响。

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.