Von Hippel-Lindau (VHL) tumour suppressor gene inactivation is linked to the development of haemangioblastomas in the central nervous system and retina, often in association with other tumours, such as clear-cell carcinomas of the kidney and phaeochromocytomas. Here we show that the VHL protein (pVHL) is a microtubule-associated protein that can protect microtubules from depolymerization in vivo. Both the microtubule binding and stabilization functions of pVHL depend on amino acids 95-123 of pVHL, a mutational 'hot-spot' in VHL disease. From analysis of naturally occurring pVHL mutants, it seems that only point mutations such as pVHL(Y98H) and pVHL(Y112H) (that predispose to haemangioblastoma and phaeochromocytoma, but not to renal cell carcinoma) disrupt pVHL's microtubule-stabilizing function. Our data identify a role for pVHL in the regulation of microtubule dynamics and potentially provide a link between this function of pVHL and the pathogenesis of haemangioblastoma and phaeochromocytoma in the context of VHL disease.
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is linked to the development of tumors of the eyes, kidneys, and central nervous system. VHL encodes two gene products, pVHL 30 and pVHL 19 , of which one, pVHL 30 , associates functionally with microtubules (MTs) to regulate their stability. Here we report that pVHL 30 is a novel substrate of glycogen synthase kinase 3 (GSK3) in vitro and in vivo. Phosphorylation of pVHL on serine 68 (S68) by GSK3 requires a priming phosphorylation event at serine 72 (S72) mediated in vitro by casein kinase I. Functional analysis of pVHL species carrying nonphosphorylatable or phosphomimicking mutations at S68 and/or S72 reveals a central role for these phosphorylation events in the regulation of pVHL's MT stabilization (but not binding) activity. Taken together, our results identify pVHL as a novel priming-dependent substrate of GSK3 and suggest a dual-kinase mechanism in the control of pVHL's MT stabilization function. Since GSK3 is a component of multiple signaling pathways that are altered in human cancer, our results further imply that normal operation of the GSK3-pVHL axis may be a critical aspect of pVHL's tumor suppressor mechanism through the regulation of MT dynamics.von Hippel-Lindau disease is a hereditary cancer syndrome that displays an autosomal dominant pattern of inheritance (2, 21). The hallmark feature of this disorder is the development of blood vessel tumors (hemangioblastomas) of the central nervous system and retina, often in association with other tumors such as renal clear cell carcinomas and pheochromocytomas. Biallelic VHL inactivation due to somatic mutations is also a common feature of nonhereditary renal clear cell carcinomas and hemangioblastomas.VHL disease demonstrates a complex genotype-phenotype relationship suggesting the operation of distinct tumor suppressor mechanisms. Indeed, pVHL, through its oxygen-dependent polyubiquitylation of HIF␣, has been shown to play a central role in the mammalian oxygen-sensing pathway (9,16,18,19,31). However, a distinct aspect of pVHL's tumor suppressor function has previously been revealed through studies demonstrating a HIF (hypoxia-inducible factor)-independent functional association of pVHL with the microtubule (MT) apparatus (14). The form of pVHL most prominently associated with MTs in vivo appears to be the long form of pVHL, pVHL 30 , and not its short form, pVHL 19 (14). pVHL 19 is mostly found in the nucleus; however, cytoplasmic pVHL 19 can bind to and stabilize MTs (14). Functional analysis of naturally occurring pVHL mutants revealed a link between altered MT stabilization function and pVHL-associated tumor-suppressing activity. In keeping with these findings, the MT-stabilizing activity of pVHL has been shown to be localized specifically to the cell periphery (29). Thus, apart from its role in oxygen sensing, pVHL also participates in the control of MT dynamics.Here we analyzed the regulation of pVHL's MT-stabilizing activity to gain further insight into this potential tumor supp...
Flaking of co-deposited layers on the inner limiter tiles was recently observed in TFTR. This phenomenon was unexpected and has occurred since the termination of plasma operations on 4 April 1997. Flaking affects approximately 15% of the observable tiles and appears on isotropic graphite but not on carbon fibre composite tiles. Photographic images of the flakes and precise measurements of the limiter geometry are reported. The mobilizability of tritium retained in co-deposited layers is an important factor in safety analyses of future DT reactors. A programme to analyse the flakes and tiles is underway.
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