SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia

Regions of hypoxia are a hallmark of solid tumors. Tumor cells modulate the regulation of specific genes allowing adaptation and survival in the harsh hypoxic environment. We have identified SKIP3, a novel human kinase-like gene, which is overexpressed in multiple human tumors and is regulated by hypoxia. SKIP3 is an ortholog of the Drosophila tribbles, rat NIPK, dog C5FW, and human C8FW genes. Drosophila tribbles is involved in slowing cell-cycle progression during Drosophila development, but little is known regarding the function or tissue distribution of the vertebrate orthologs. We show that the normal tissue expression of SKIP3 is confined to human liver, while multiple primary human lung, colon, and breast tumors express high levels of SKIP3 transcript. Endogenous SKIP3 protein accumulates within 48 h under hypoxic growth conditions in HT-29 and PC-3 cells, with upregulation of the SKIP3 mRNA transcript by 72 h. We identified activating transcription factor 4 (ATF4) as a SKIP3-binding partner using the yeast-two-hybrid assay. Coexpression of SKIP3 and ATF4 showed that SKIP3 is associated with the proteolysis of ATF4, which can be blocked using a proteosome inhibitor. These results indicate that SKIP3 may be an important participant in tumor cell growth.