Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor ␣ subunits (HIF-1␣ and HIF-2␣), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1␣ and HIF-2␣ in RCC and non-RCC cells. We demonstrate common patterns of HIF-␣ isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-␣ isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2␣ suppressing HIF-1␣ and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2␣ and that the proapoptotic gene encoding BNip3 responds positively to HIF-1␣ and negatively to HIF-2␣, indicating that HIF-1␣ and HIF-2␣ have contrasting properties in the biology of RCC. In keeping with this, HIF-␣ isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1␣ retarding and HIF-2␣ enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions.

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The Central Asian Orogenic Belt records the accretion and convergence of three collage systems that were finally rotated into two major oroclines. The Mongolia collage system was a long, N–S-oriented composite ribbon that was rotated to its current orientation when the Mongol-Okhotsk orocline was formed. The components of the Kazakhstan collage system were welded together into a long, single composite arc that was bent to form the Kazakhstan orocline. The cratons of Tarim and North China were united and sutured by the Beishan orogen, which terminated with formation of the Solonker suture in northern China. All components of the three collage systems were generated by the Neoproterozoic and were amalgamated in the Permo-Triassic. The Central Asian Orogenic Belt evolved by multiple convergence and accretion of many orogenic components during multiple phases of amalgamation, followed by two phases of orocline rotation.

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