Mechanisms of the HBX-interacting protein (HBXIP)

描述（由申请人提供）：慢性乙型肝炎病毒（HBV）感染影响全球约4亿人，每年有超过100万人死于肝细胞癌（HCC）。HBV基因组仅包含4个开放阅读框，分别编码C、S和X蛋白以及DNA聚合酶。其中，只有HBx蛋白与癌症有关。HBx癌蛋白的细胞靶点包括HBx相互作用蛋白（HBXIP）。最近，我们证明HBXIP与Survivin相互作用，Survivin是一种在大多数人类癌症中过度表达的蛋白，调节细胞分裂和凋亡。HBXIP与Survivin协同抑制细胞凋亡。初步数据还表明，HBXIP定位于分裂细胞中的有丝分裂结构，与Survivin一样，是有丝分裂和细胞分裂所必需的。基于这些发现，我们推测HBXIP是Survivin的重要伙伴，是细胞分裂和凋亡的双重调节因子。我们还假设病毒蛋白HBx靶向HBXIP，从而失调Survivin的功能。为了验证这些假设，我们将：(1)确定HBXIP调节细胞分裂和凋亡的机制；(2)探讨HBx对HBXIP-Survivin相互作用以及与凋亡和细胞周期调节相关的功能的影响。总之，这些研究将明确HBXIP在调节细胞分裂和凋亡中的作用，并为HBx在HCC发病中的机制提供新的见解。

DESCRIPTION (provided by applicant): Chronic Hepatitis B Virus (HBV) infection affects approximately 400 million people worldwide, and is associated with over one million deaths per year clue to hepatocellular carcinoma (HCC). The HBV genome contains only four open reading frames, encoding the C, S, and X proteins, and DNA polymerase. Among these, only the HBx protein has an association with cancer. The cellular targets of the HBx oncoprotein include the HBx-interacting protein (HBXIP). Recently, we demonstrated that HBXIP interacts with Survivin, a protein over-expressed in most human cancers that regulates both cell division and apoptosis. HBXIP collaborates with Survivin in suppressing apoptosis. Preliminary data also indicate that HBXIP localizes to mitotic structures in dividing cells, and like Survivin, it is required for mitosis and cell division. Based on these findings, we hypothesize that HBXIP is an important partner of Survivin and a dual regulator of cell division and apoptosis. We also hypothesize that the viral protein HBx targets HBXIP, thereby dysregulating the function of Survivin To test these hypotheses, we will: (1) determine the mechanisms by which HBXIP regulates cell division and apoptosis; and (2) explore the effects of HBx on HBXIP-Survivin interactions and functions associated with apoptosis and cell cycle regulation. Altogether, these investigations will define the role of HBXIP in regulating cell division and apoptosis, as well as providing new insights into the mechanisms of HBx in the pathogenesis of HCC.