共查询到20条相似文献,搜索用时 31 毫秒
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Jia Li Wanlin Xi Xiaofang Li Haiying Sun Yuyan Li 《Bioorganic & medicinal chemistry》2019,27(7):1145-1158
Hypoxia is a common characteristic of many types of solid tumors and is associated with tumor propagation, malignant progression, and resistance to anti-cancer therapy. HIF-1 pathway is one of the survival pathways activated in tumor in response to hypoxia. In hypoxic condition, hypoxia-inducible factor-1α (HIF-1α) is stabilized and translocated into nucleus where it forms heterodimer with HIF-1β and regulates the expression of a plethora of genes involved in different processes, such as cell proliferation, differentiation, apoptosis, vascularization/angiogenesis, tumor invasion and metastasis. Recruitment of co-activator p300 or CBP to HIF-1α is critical to the transactivation activity of HIF-1 dimer, therefore, small molecules which can block the dimerization of HIF-1α and HIF-1β or inhibit the interaction between HIF-1α and p300 can function as inhibitors of HIF-1 and have the potential to be developed as novel therapies for the treatment of human cancers. In this review, recent progress of small molecular inhibitors of protein-protein interactions targeting HIF-1 is summarized, the mechanism of functions of these compounds and their potential usage as anti-cancer agents have also been discussed. 相似文献
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HIF-1α plays a central role in cellular adaptation to hypoxia, and is closely related to the pathogeneses of life-threatening disorders. HIF-1α induces the expressions of numerous hypoxia-induced genes through two transactivation domains; N-terminal TAD (NAD) and C-terminal TAD (CAD). Furthermore, p300 is known to boost CAD-dependent transactivation, and CBP/p300-interacting transactivator with an ED-rich tail 2 (CITED2) inhibits HIF-1α-driven gene expression by interfering with the interaction between CAD and p300. However, few researches have focused on the role of CITED2 in the regulation of NAD activity, and thus, we addressed this point. CITED2 was found to attenuate the hypoxic activations of NAD-dependent and CAD-dependent genes, suggesting that CITED2 negatively regulates both CAD and NAD. Immunoprecipitation analyses showed that NAD interacts with the Cystein/Histidine region (CH) 1 and CH3 domains of p300. Moreover, CH1 and CH3 both were required for NAD-dependent transactivation. Furthermore, CITED2 was found to inactivate NAD by interfering with NAD binding to CH1, but not to CH3. These results indicate that CITED2 inactivates HIF-1α by blocking p300 recruitment by both NAD and CAD. We also found that pVHL inhibits NAD activity regardless of NAD degradation by blocking the interaction between p300 and NAD. Summarizing, NAD was activated by binding to p300, and this was blocked by either CITED2 or pVHL. We propose that pVHL controls NAD during normoxia and that CITED2 controls NAD during hypoxia. Our results provide a new strategy for controlling HIF-1α. 相似文献
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MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300 总被引:23,自引:0,他引:23
Sang N Stiehl DP Bohensky J Leshchinsky I Srinivas V Caro J 《The Journal of biological chemistry》2003,278(16):14013-14019
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Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression 总被引:6,自引:0,他引:6
Kasper LH Boussouar F Boyd K Xu W Biesen M Rehg J Baudino TA Cleveland JL Brindle PK 《The EMBO journal》2005,24(22):3846-3858
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Regulation of gene expression by the hypoxia-inducible factors 总被引:1,自引:0,他引:1
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Warnecke C Weidemann A Volke M Schietke R Wu X Knaup KX Hackenbeck T Bernhardt W Willam C Eckardt KU Wiesener MS 《Experimental cell research》2008,314(10):2016-2027
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