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基因，在包括白血病在内的多种恶性肿瘤中经常发生突变。PRb及其相关蛋白p107和p130与转录因子E2F家族的不同成员结合并失活。除了E2F外，pRb还可以与其他调节pRb-E2F复合体转录活性的因子相互作用，如hbp1(hMG-box含转录抑制因子)、hBRG1和hBRM(SNF2/SWI2酵母转录激活剂的哺乳动物同源物)，以及组蛋白脱乙酰基酶(参与染色质结构重排的酶)，都被报道与pRb相互作用并调节其转录活性。这些调节剂中的每一个都以LXCXE基序依赖的方式与PRB结合。LXCXE基序最初在某些已知与pRb结合的病毒癌蛋白(SV40T抗原、HPV-16E7、腺病毒E1a)中发现。我们实验室的初步结果表明，pRb也可能与HMG1/2类蛋白相互作用。HMG蛋白是染色质的核非组蛋白结构元件，含有LXCXE基序。我们建议研究HMG类蛋白质是否参与依赖于pRB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HMG2和PRB的特异性关联。为了探讨HMG2/PRB相互作用的功能意义，我们将在模型实验中检测HMG对PRB转录抑制能力的影响。

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.