PMID- 10441001
OWN - NLM
STAT- MEDLINE
DCOM- 19990827
LR  - 20061115
IS  - 1045-2257 (Print)
IS  - 1045-2257 (Linking)
VI  - 26
IP  - 1
DP  - 1999 Sep
TI  - Genomic organization and chromosomal localization of the human CUL2 gene and the 
      role of von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1)
      mutation and loss in renal-cell carcinoma development.
PG  - 20-8
AB  - Germline mutations in the von Hippel-Lindau (VHL) disease tumor suppressor gene
      (TSG) convey a high risk of clear-cell renal-cell carcinoma (CC-RCC) and most
      sporadic CC-RCCs demonstrate somatic inactivation of the VHL TSG. However, the
      existence of further CC-RCC gatekeeper genes is implied by CC-RCC kindreds not
      linked to the VHL gene and the absence of somatic VHL inactivation in
      approximately 30% of sporadic CC-RCC. Genes that encode proteins which interact
      with the VHL gene product (VHL) provide candidate gatekeeper RCC genes. VHL forms
      a multimeric complex with two subunits (B and C) of the SIII (elongin)
      transcriptional elongation complex and CUL2, a member of the cullin family. Most 
      pathogenic VHL mutations inhibit formation of the VHL/elonginB+C/CUL2 complex. A 
      further VHL-binding protein of unknown function, VBP1, fails to bind to truncated
      forms of VHL. We have investigated the possible roles of CUL2 and VBP1 in renal
      tumorigenesis by analyzing sporadic RCC of known VHL mutation or hypermethylation
      status, including CC-RCC without VHL inactivation (n = 40); CC-RCC with VHL
      inactivation (n = 35); and non-CC-RCC (n = 14). No VBP1 mutations were identified
      in 89 sporadic RCCs, suggesting that VBP1 is not an RCC gatekeeper gene. To
      investigate CUL2, we mapped the CUL2 gene to chromosome band 10p11.1-p11.2, a
      region reported to show loss of heterozygosity (LOH) in several human cancers
      (including non-CC-RCC); determined the genomic organization; and performed
      mutation analysis of the 21 exons identified. Using novel intragenic
      polymorphisms, we detected LOH in 6/25 informative RCCs; however, no pathogenic
      CUL2 mutations were identified in the 89 RCCs analyzed. These findings suggest
      that unless CUL2 is inactivated by epigenetic events, it is not a major RCC TSG. 
      However, CUL2 remains a candidate TSG for other tumor types demonstrating 10p
      LOH. Genes Chromosomes Cancer 26:20-28, 1999.
CI  - Copyright 1999 Wiley-Liss, Inc.
FAU - Clifford, S C
AU  - Clifford SC
AD  - Section of Medical and Molecular Genetics, Department of Paediatrics and Child
      Health, University of Birmingham, Birmingham, U.K.
FAU - Walsh, S
AU  - Walsh S
FAU - Hewson, K
AU  - Hewson K
FAU - Green, E K
AU  - Green EK
FAU - Brinke, A
AU  - Brinke A
FAU - Green, P M
AU  - Green PM
FAU - Gianelli, F
AU  - Gianelli F
FAU - Eng, C
AU  - Eng C
FAU - Maher, E R
AU  - Maher ER
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Genes Chromosomes Cancer
JT  - Genes, chromosomes & cancer
JID - 9007329
RN  - 0 (CUL2 protein, human)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Cullin Proteins)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (VBP1 protein, human)
SB  - IM
MH  - Carcinoma, Renal Cell/*genetics
MH  - Carrier Proteins/*genetics/physiology
MH  - Cell Cycle Proteins/*genetics/physiology
MH  - Chromosome Mapping
MH  - Chromosomes, Human, Pair 10/genetics
MH  - *Cullin Proteins
MH  - DNA Mutational Analysis
MH  - DNA, Neoplasm/chemistry/genetics
MH  - Exons
MH  - Genes/*genetics
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Introns
MH  - Kidney Neoplasms/*genetics
MH  - Loss of Heterozygosity
MH  - Mutation
MH  - Point Mutation
MH  - Polymorphism, Genetic
MH  - Polymorphism, Restriction Fragment Length
MH  - Polymorphism, Single-Stranded Conformational
MH  - Sequence Analysis, DNA
EDAT- 1999/08/10 00:00
MHDA- 1999/08/10 00:01
CRDT- 1999/08/10 00:00
PHST- 1999/08/10 00:00 [pubmed]
PHST- 1999/08/10 00:01 [medline]
PHST- 1999/08/10 00:00 [entrez]
AID - 10.1002/(SICI)1098-2264(199909)26:1<20::AID-GCC3>3.0.CO;2-6 [pii]
PST - ppublish
SO  - Genes Chromosomes Cancer. 1999 Sep;26(1):20-8.