Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity

Blankenship, Catherine; Naglich, Joseph G.; Whaley, Jean M.; Seizinger, Bernd R.; Kley, Nikolai

doi:10.1038/sj.onc.1202473

Cited by 129 publications

(70 citation statements)

References 24 publications

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“…VHL gene produces two wild-type forms, a full-length VHL30 and an internally translated VHL19. [33][34][35] Although ectopic expression of either isoform has been shown to suppress CC-RCC tumor formation in Nude mice, 10,11,33,35 demonstrating that both isoforms possess tumor suppressor functions, VHL19 is more abundantly produced than VHL30. Therefore, the general perception is that VHL19 is the dominant isoform, at least, in cell lines.…”

Section: The Synthetic Vhl19 Mutant Exhibits the Biochemical Signaturmentioning

confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC. [4][5][6][7] Currently, a prediction of patient survival is based on traditional clinical parameters, including tumor size and Fuhrman nuclear grade. 8 However, the emerging understanding of the molecular pathways implicated in CC-RCC genesis and progression is providing previously unappreciated markers, which may serve as additional or better prognostic indicators of CC-RCC.The principal cause of sporadic CC-RCC and familial von Hippel-Lindau (VHL) disease-associated CC-RCC is the inactivating mutations of VHL. Although VHL patients also develop tumors in other organs including the central nervous system, retina and the adrenal gland, CC-RCC remains to be the leading cause of morbidity and death for VHL patients. 9 The most well-established function of VHL is its role in the oxygen-dependent negative regulation of hypoxia-inducible factor (HIF). VHL is a substrate-conferring component of an E3 ubiquitin ligase ECV (elongins/Cul2/VHL) that polyubiquitylates the catalytic a-subunit of HIF that has undergone hydroxylation on conserved prolyl residues within the oxygen-dependent degradation (ODD) domain. Prolyl hydroxylation is mediated by a class of prolyl hydroxylases (PHD1-3) in an oxygen-dependent manner. Thus, under hypoxia or in the absence of a functional VHL, HIFa becomes stabilized and binds to its common and constitutively expressed b-subunit, forming an active HIF transcription factor capable of transactivating numerous hypoxia-inducible genes such as vascular endothelial growth factor (VEGF),

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Section: The Synthetic Vhl19 Mutant Exhibits the Biochemical Signaturmentioning

confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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“…Human VHL mRNA can be translated from either the ®rst or the second methionines and gives two proteins with apparent molecular masses of 28 ± 30 kD (long form) and 18 ± 19 kD (short form) respectively (Blankenship et al, 1999;Iliopoulos et al, 1998;Schoenfeld et al, 1998). Despite the absence of the N-terminal 53 amino acids in the short form of the protein, no signi®cant di erences in their biochemical properties or tumor suppressor function have been reported.…”

Section: Resultsmentioning

confidence: 99%

Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth

Hirai

Kawakami

et al. 2001

Oncogene

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In spite of the general recognition of von Hippel-Lindau (VHL) as a tumor suppressor gene, the physiological and pathological importance of VHL protein in cell growth regulation and tumorigenesis remains unclear. Here we show that in normal human renal proximal tubule epithelial cells (RPTEC), the steady-state amount of VHL protein is strictly regulated by cell density. The cellular VHL content is more than 100-fold higher in dense cultures than in sparse cultures. The increase in VHL protein at high cell density was also observed for NIH3T3 ®broblasts, suggesting the generality of the phenomenon. The growth rates of renal cell carcinoma cells lacking an intact VHL gene and their derivatives with wild-type or mutant VHL expression vector do not di er signi®cantly when they are growing in log-phase. Importantly, however, there is a di erence when they reach con¯uency: cells lacking wild-type VHL grew continuously, while cells expressing exogenous VHL protein showed relatively limited cell growth. Using an ecdysone-inducible VHL expressing cell line, we also show that the growth inhibition at high cell density can be released by attenuating the VHL expression. Taken together, we propose that VHL protein functions as a growth suppressor at high cell density, and this might be the basis of the tumor suppressor function of VHL.

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“…However, no functional signi®cance has been assigned to the extra 53 amino acids at the N-terminus of the large h-VHL. Underlying this fact are the following observations: First, the short h-VHL is su cient for the tumor suppressor function (Schoenfeld et al, 1998;Blankenship et al, 1999). Second, no clinically relevant mutations have been mapped in the N-terminus (Beroud et al, 1998).…”

Section: D-vhl Gain-of-function Phenotypesmentioning

confidence: 99%

Tracheal development and the von Hippel–Lindau tumor suppressor homolog in Drosophila

et al. 2000

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Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity

Cited by 129 publications

References 24 publications

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth

Tracheal development and the von Hippel–Lindau tumor suppressor homolog in Drosophila

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