DNA损伤应答相关蛋白Bclaf1在HIF1低氧应激系统中的作用

HIF1介导的低氧应激体系，不仅具有重要的生理功能，而且该系统的失调在肿瘤的发展中起着重要作用，是肿瘤治疗中十分具有前景的靶系统，但HIF1的活性在低氧条件是如何受到有效调控的还不清楚。Bclaf1是一个和细胞凋亡、DNA损伤应答以及肿瘤发生密切相关的重要蛋白，但其在肿瘤发生中的具体作用也不清楚。我们前期的一些实验结果显示Bclaf1是一个表达受低氧调控的蛋白，而且有可能参与了低氧条件下HIF1稳定性调控。我们推测HIF1的稳定性在低氧条件需要一种正反馈机制来加以维持，而Bclaf1在该过程中起着关键作用。在本申请项目中我们拟深入研究Bclaf1在低氧应激中的作用和机制。具体研究内容包括：1）低氧刺激上调Bclaf1的分子机制；2）HIF1在低氧条件下的降解机制以及Bclaf1对该机制的拮抗作用；3）Bclaf1在细胞及肿瘤生长中的作用及与HIF1的关系。

The hypoxia-inducible factor 1 (HIF1) is the master regulator of the cellular response to hypoxia, which have important physiological functions and are intimately related to tumor progression. The HIF1 system has a great potential as drug targets in anti-tumor therapies. However, how HIF1 is regulated in hypoxic condition is not well understood. Bclaf1 (Bcl2 associated transcription factor) is a protein that is involved in apoptosis, DNA damage response and tumorigenesis, and yet its exact function in tumorigenesis is no clear. We found in our preliminary studies that Bclaf1 was upregulated in response to hypoxic treatment in multiple cancer cell lines, and that knockdown of Bclaf1 greatly reduced the stability of HIF1 in hypoxic condition. We therefore speculate that the activity of HIF1 in hypoxic condition requires a positive feedback mechanism to maintain, in which Bclaf1 plays a critical role. In this proposal we plan to test this hypothesis aiming to elucidate the role of Bclaf1 in hypoxic response and the underlying mechanism. Specifically, we plan to investigate: 1) the mechanism that is responsible for Bclaf1 upregulation in hypoxic treatment; 2) the mechanism that induces HIF1 degradation in hypoxic condition and the role of Bclaf1 antagonizing this action; and 3) the role of Bclaf1 in cell and tumor growth and its relationship to HIF1. These studies will provide insights into HIF1 regulation and role of Bclaf1 in tumorigenesis.