The VHL gene is made up of 639 nucleotides, consisting of three exons that generate two mRNA species. The larger one of 4.6 kb corresponds to all three exons and generates a full-length 213-amino acid protein which is expressed in most tissues and has been implicated in a variety of functions including fibronectin matrix assembly, angiogenesis, and regulation of hypoxia-inducible genes. The VHL gene product (pVHL) is a component of a ubiquitin ligase which targets the transcription factor hypoxia-inducible factor (HIF) subunits HIF-1a and HIF-2a for ubiquitination and proteolytic degradation in the presence of oxygen, by forming a ubiquitin-ligase complex with elongin B and C, as well as Cullin-2 and Rbx1 (reviewed in Ref. ).
There are two main domains of pVHL, the a helical domain interacting with elongin C, and the b domain where binding to HIF takes place. Generally, cells defective for pVHL (resulting from VHL inactivation) cannot degrade HIF-a subunits leading to the transcrip-tional activation of HIF target genes such as vascular endothelial growth factor. This is consistent with the angiogenic nature of VHL-associated tumors.
The role of pVHL in oxygen-sensing pathways and the highly vascularized nature of the tumors seen in VHL may, in the future, extend the clinical management options discussed above to include molecular drugs designed to inhibit HIF and/or its downstream targets. Early studies have suggested that these inhibitory drugs may work best in concert with other molecular drugs targeting cellular growth and survival pathways with the aim of achieving tumor regression and/or disease stabilization (reviewed in Ref. ).
ing the degradation of the target proteins such as HIF-a in the proteosome (Fig. 1B). For Type 2C families with PHEO as the only expression of VHL disease, the missense mutations are generally clustered in the VHL a domain. It has been demonstrated that mutants such as L188V with an increased likelihood of PHEO-only phenotype can downregulate HIF but cannot promote fibronectin matrix assembly. This suggests that after pVHL inactivation abnormal fibronectin assembly may contribute to PHEO pathogenesis in VHL disease.
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The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.