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

M, Baba; Hirai, Syu-ichi; Kawakami, Satoshi; Kishida, Takeshi; Sakai, Naoki; Kaneko, Shotaro; Yao, Masahiro; Shuin, Taro; Kubota, Yoshinobu; Hosaka, Masahiko; Ohno, Shigeo

doi:10.1038/sj.onc.1204397

Cited by 47 publications

(29 citation statements)

References 48 publications

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“…Consistent with our finding, Baba et al (2001) also showed that the expression of pVHL is cell densitydependent. They reported that VHL negative renal carcinoma cells continued to grow after attaining confluence and that VHL positive cells underwent cell cycle arrest.…”

Section: Discussionsupporting

confidence: 81%

von Hippel–Lindau protein complex is regulated by cell density

Mohan

Burk

2003

Oncogene

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Mutations in the von Hippel-Lindau (VHL) gene are involved in the VHL family cancer syndrome and sporadic renal cell carcinoma. Previous studies indicated that VHL-induced growth arrest required high cell density and growth on extracellular matrix. In the present study, VHL protein (pVHL) levels were observed to be dramatically increased in cells grown to high cell density compared to cells grown at low cell density. Reverse transcription-polymerase chain reaction and Northern blot analysis indicated that VHL mRNA levels were equivalent in sparse and dense cells. The pVHL was rapidly degraded when cell-cell contact was disturbed by trypsinization or EDTA release. Treatment of cells with a proteasome inhibitor blocked the degradation of pVHL. Using a set of VHL deletions fused to GFP, a cell densitydependent region (CDDR) was identified and localized to the c-terminus of pVHL. In addition, other members of the VBC protein complex also showed a cell densitydependent regulation similar to pVHL. Cell density regulation of VHL did not require elongin binding and density-dependent regulation of other VBC components was not dependent on pVHL. In addition, hypoxia inducible factor-2a protein levels were elevated in sparse cells with low levels of pVHL and reduced or absent in confluent cells containing abundant VHL. These results indicate that pVHL levels and thus function are tightly regulated by cell-cell signaling. In addition, care must be taken when interpreting studies of VHL function and subcellular localization of cells grown at subconfluent conditions.

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Section: Discussionsupporting

confidence: 81%

von Hippel–Lindau protein complex is regulated by cell density

Mohan

Burk

2003

Oncogene

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“…pVHL has been reported to have a number of biochemical functions, including regulation of microtubule stability, cell differentiation, cell motility, extracellular matrix assembly, JunB, and atypical isoforms of protein kinase C (15,(17)(18)(19)(20)(21)(22). However, the best characterized function of pVHL is to act as an essential component in the degradation of HIF-␣ subunits (10,14).…”

Section: Resultsmentioning

confidence: 99%

Formation of Primary Cilia in the Renal Epithelium Is Regulated by the von Hippel-Lindau Tumor Suppressor Protein

Esteban¹,

Harten²,

Tran³

et al. 2006

Journal of the American Society of Nephrology

147

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Growing evidence points to defects in the primary cilium as a critical mechanism underlying renal cyst development. Inactivation of the VHL gene is responsible for the autosomal dominant condition von Hippel-Lindau (VHL) disease and is implicated in most sporadic clear cell renal carcinomas. Manifestations of VHL disease include cysts in several organs, particularly in the kidney. Here it is shown that VHL inactivation is associated with abrogation of the primary cilium in renal cysts of patients with VHL disease and in VHL-defective cell lines. Complementation of VHL-defective clear cell renal carcinoma cell lines with wild-type VHL restored primary cilia. Moreover, it is shown that the effects of VHL on the primary cilium are mediated substantially via hypoxia-inducible factor. The effect of VHL status on the primary cilium provides a potential mechanism for renal cyst development in VHL disease and may help in the understanding of how VHL acts as a tumor suppressor.

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“…In fact, VHL disease-associated pheochromocytoma has been speculated to develop as a result of a gain of function of pVHL, as this tumor type is almost exclusively observed in the setting of missense mutations (34). Furthermore, several activities have been ascribed to pVHL in addition to the regulation of the hypoxia response pathway and were recently reviewed (35), including potential function in cell cycle regulation (36 -38), cell growth (39,40), cytoskeletal structure (41,42), and extracellular matrix deposition (43). In this report we take advantage of genotype-phenotype correlation, and we have complemented Vhl Ϫ/Ϫ embryonic stem cells with a selected group of mutations representing the various subtypes of VHL disease, including Chuvash Polycythemia, to dissect potentially distinct activities of pVHL that are intrinsic to tissue-specific tumor types seen in the hereditary disease.…”

Section: Introductionmentioning

confidence: 99%

In vitro and In vivo Models Analyzing von Hippel-Lindau Disease-Specific Mutations

et al. 2004

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Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene cause tissue-specific tumors, with a striking genotype-phenotype correlation. Loss of VHL expression predisposes to hemangioblastoma and clear cell renal cell carcinoma, whereas specific point mutations predispose to pheochromocytoma, polycythemia, or combinations of hemangioblastoma, renal cell carcinoma, and/or pheochromocytoma. The VHL protein (pVHL) has been implicated in many cellular activities including the hypoxia response, cell cycle arrest, apoptosis, and extracellular matrix remodeling. We have expressed missense pVHL mutations in Vhl Ϫ/Ϫ murine embryonic stem cells to test genotype-phenotype correlations in euploid cells. We first examined the ability of mutant pVHL to direct degradation of the hypoxia inducible factor (HIF) subunits HIF1␣ and HIF2␣. All mutant pVHL proteins restored proper hypoxic regulation of HIF1␣, although one VHL mutation (VHL R167Q ) displayed impaired binding to Elongin C. This mutation also failed to restore HIF2␣ regulation. In separate assays, these embryonic stem cells were used to generate teratomas in immunocompromised mice, allowing independent assessment of the effects of specific VHL mutations on tumor growth. Surprisingly, teratomas expressing the VHL Y112H mutant protein displayed a growth disadvantage, despite restoring HIF␣ regulation. Finally, we observed increased microvessel density in teratomas derived from Vhl Ϫ/Ϫ as well as VHL Y112H , VHL R167Q , and VHL R200W embryonic stem cells. Together, these observations support the hypothesis that pVHL plays multiple roles in the cell, and that these activities can be separated via discrete VHL point mutations. The ability to dissect specific VHL functions with missense mutations in a euploid model offers a novel opportunity to elucidate the activities of VHL as a tumor suppressor.

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

Cited by 47 publications

References 48 publications

von Hippel–Lindau protein complex is regulated by cell density

von Hippel–Lindau protein complex is regulated by cell density

Formation of Primary Cilia in the Renal Epithelium Is Regulated by the von Hippel-Lindau Tumor Suppressor Protein

In vitro and In vivo Models Analyzing von Hippel-Lindau Disease-Specific Mutations

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