BioProject

Activation of the hypoxia inducible transcription factor HIF-alpha and the NF-kappaB pathway promotes inflammation mediated tumor progression. More...

Activation of the hypoxia inducible transcription factor HIF-alpha and the NF-kappaB pathway promotes inflammation mediated tumor progression. The cellular transcription factor ZNF395 was repeatedly found over expressed in various human cancers and particularly in response to hypoxia, implying a functional relevance. To understand the biological activity of ZNF395, we identified target genes of ZNF395 by a genome-wide expression screen. Induced ZNF395 expression let to up-regulation of a subset of interferon (IFN)-responsive genes such as IFIT1/ISG56 and IFI44 as well as genes known to be involved in cancer progression including MEF2C and MACC1. ZNF395 requires its DNA binding domain and the two IFN-sensitive-response elements within the IFIT1/ISG56 promoter to activate. We provide evidence that IkBa kinase-mediated phosphorylation is required to allow activation of transcription by ZNF395 but simultaneously accelerates it for proteolytic degradation to keep the activity of ZNF395 transient and weak. We further confirm that ZNF395 is induced by hypoxia. Thus, two crucial pathways contributing to cancers progression, i.e. hypoxia and inflammation cooperate in activation of ZNF395 at the level of transcription and post-translational modification. Increased amounts of transcriptional active ZNF395 in cancers may support carcinogenesis by activating its target genes associated with the innate immune response and cancer. Overall design: 4 samples treated with doxycycline-induced ZNF395 were compared to 4 untreated controls Less...