Fig. 3

WSB1 has Diverse Roles in Hypoxia That May Also Drive Cancer Cell Growth. This figure summarizes the varied roles that WSB1 performs in the cellular response to hypoxia in cancer cells. In the normal hypoxic response, low oxygen results in inhibition of the VHL protein, which normally facilitates the degradation of the alpha subunit of the main hypoxia transcription factor HIF-1. HIF-1 upregulates a wide variety of target genes through interaction with its consensus Hypoxia Response Element, including wsb1, and a variety of other genes which can lead to enhanced cellular survival and metastasis in cancer cells. Upregulation of wsb1 results in enhanced degradation of the VHL protein through WSB1, and increased activity of HIF-1, as well as increased degradation of other WSB1 targets HIPK2 and RhoDGI2, the effects of which can also stimulate cancer cell growth and metastasis. Aside from upregulation of the many HIF-1 target genes associated with the cellular response to hypoxia, HIF-1 also upregulates many of the genes whose products mediate the Warburg effect of glucose metabolism in cancer cells. The microRNA, miR-592, downregulates WSB-1 and thus can modulate the Warburg effect and the response to hypoxia. In summary, recent characterization of diverse roles for WSB1 in the cellular response to hypoxia suggests that WSB1 may function as an oncogene, leading to enhanced cancer cell survival and metastasis through a variety of physiologic roles