Direct Interaction of the β-Domain of VHL Tumor Suppressor Protein with the Regulatory Domain of Atypical PKC Isotypes

Okuda, Heiwa; Hirai, Syu-ichi; Takaki, Yasuyuki; Kamada, Masayuki; M, Baba; Sakai, Naoki; Kishida, Takeshi; Kaneko, Shotaro; Yao, Masahiro; Ohno, Shigeo; Shuin, Taro

doi:10.1006/bbrc.1999.1347

Cited by 90 publications

(63 citation statements)

References 34 publications

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“…Un-®xed cells were stained with Trypan blue to certify that most of the cells were alive (data not shown). Bars, 30 mm PKCs and the VHL protein has been reported, and is known to be involved in the regulation of cell growth or apoptosis (Okuda et al, 1999;Pal et al, 1997). VHL also acts as a Nedd8 ligase for Cul-2, which may be involved in cell cycle regulation (Feng et al, 1999;Liakopoulos et al, 1999;Wada et al, 1999).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…d-VHL has an overall 22% identity to h-VHL and is 50% similar when conserved amino acid changes were considered ( Figure 1b). In the two functionally signi®cant protein interaction domains, human residues 113 ± 121 and 157 ± 172 that encompass the protein kinase Cl (PKCl) and the elongin C binding sites, respectively (Okuda et al, 1999;Kibel et al, 1995), the conservation is signi®cantly higher at 67 and 76%.…”

Section: Cloning Of the D-vhl Gene Sequencementioning

confidence: 99%

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

et al. 2000

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“…These reports suggest that PHE in VHLD requires a reduction in the ability of pVHL to facilitate apoptosis rather than an impairment of HIF degradation. The same group previously reported that the β domain of pVHL interacted with the regulatory domain of atypical protein kinase C (PKC) isotypes and was required for apoptosis regulation [23]. In our study, the detection of the N131S mutation at the region encoding the β domain and not the region encoding the α domain of pVHL may support the latter hypothesis; this indicates that PHE in VHLD with the N131S mutation may be caused by the reduced apoptosis of the neural crest cells rather than reduced HIF degradation.…”

Section: Discussionmentioning

confidence: 97%

The N131S Mutation in the von Hippel-Lindau Gene in a Japanese Family with Pheochromocytoma and Hemangioblastomas

et al. 2006

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Abstract. Von Hippel-Lindau (VHL) disease (VHLD) is a hereditary autosomal dominant syndrome that causes various benign and malignant tumors. VHLD is caused by mutations in the VHL tumor suppressor gene. Here, we report a mutation in the VHL gene in a Japanese family with VHLD type 2A, characterized by pheochromocytoma (PHE), and hemangioblastomas (HAB) in both the retina and thoracic spinal cord but without renal cell carcinoma (RCC). We identified a heterozygous A to G point mutation at the second base of codon 131 of the VHL protein (pVHL). This mutation was predicted to convert codon 131 from asparagine to serine (N131S). Although most mutations in VHLD type 2A have been detected in the α domain of pVHL, the present mutated amino acid was located at the region encoding the β domain of pVHL. Previous patients with the N131K or N131T mutation in pVHL developed VHLD type 2B with RCC or VHLD type 1 without PHE, respectively. We also identified somatic loss of heterozygosity (LOH) at chromosome 3p25-26 in the adrenal tumor of the patient. The results of our study suggest that not only the location of mutation but also the altered amino acid may be critical for determining the clinical phenotype of VHLD. LOH was associated with the development of PHE in a patient with the N131S mutation in pVHL.

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Direct Interaction of the β-Domain of VHL Tumor Suppressor Protein with the Regulatory Domain of Atypical PKC Isotypes

Cited by 90 publications

References 34 publications

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

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

The N131S Mutation in the von Hippel-Lindau Gene in a Japanese Family with Pheochromocytoma and Hemangioblastomas

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