Cloning Tumor Suppressor Genes (TSG) From Human Chromosomes 3p and 8p

Lerman, M.

Abstract

The goal of this research is to identify,clone,and characterize TSGs located on chromosomes 3p and 8p that are involved in the origin or development of major human malignancies: carcinomas of the lung, breast,kidney, and prostate. Our major accomplishments this year are: (1) assembly of the complete sequence of the VHL gene (GenBank #AFO10238);(2) identification of pVHL target genes by differential display technology; to date 25% of the cell transcibed genes were analyzed and six down regulated genes identified, namely,NOTCH 2,that specifies cell fate determination,RACK 1 an intracellular receptor for PKC, CA9 and10 (members of the carbonic anhydrase superfamily), and two new unknown genes. (3) analysis of the methylation of the VHL promoter in renal carcinoma:monochromosome gene transfer, cell fusion, and VHL gene transfections showed that the meth+ phenotype is dominant. (4)The 3p21.3 TSG:the 370kb critical region defined and sequenced last year is now narrowed to 120kb by a newly discovered overlapping deletion.Eight new genes reside in this region,including a new alpha2- delta subunit of the L-type calcium channel that appears to elicit autoantibodies in LEMS (Lambert - Eaton myastenic syndrom) associated with SCLC. These genes are being analyzed for mutations, expression,imprinting, and the ability to suppress growth of target cancer cells. (5)The 3p12 TSG: a candidate gene that is a new member of the cell adhesion molecule superfamily (CAMs) and showed homology to the TSG DCC is being analyzed (6)The 3p25-p26 TSG:using in silico location cloning a new member of CAMs,CALL,was isolated and analysed (GenBank #AFO02246).(7)The 8p22 TSG: products of two classical TSGs, NF1 and TSC2 are large GTPase activating proteins (GAPs) for RAS and RAP1 respectively.To discover other GAPs we searched NCBI databases for ESTs representing such genes in TSGs regions defined by LOH on chromosomes 8p and 1p.We have now isolated and characterized the human ortholog of the rat p122RhoGAP, which is a dual regulator of Rho and PLC delta. This gene is localized by us to 8p22 (GenBank # AFO26219) and is a candidate TSG for lung, breast, and prostate cancers.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Intramural Research (Z01)
• Project #: 1Z01BC008579-04
• Application #: 6161019
• Study Section: Special Emphasis Panel (LIB)
• Support Year: 4
• Fiscal Year: 1997

Institution

• Name: National Cancer Institute Division of Basic Sciences
• Country: United States

Publications

Ivanov, Sergey V; Ivanova, Alla V; Salnikow, Konstantin et al. (2008) Two novel VHL targets, TGFBI (BIGH3) and its transactivator KLF10, are up-regulated in renal clear cell carcinoma and other tumors. Biochem Biophys Res Commun 370:536-40

Angeloni, D; Danilkovitch-Miagkova, A; Ivanova, T et al. (2007) Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter. Oncogene 26:4499-512

Ivanova, A V; Ivanov, S V; Pascal, V et al. (2007) Autoimmunity, spontaneous tumourigenesis, and IL-15 insufficiency in mice with a targeted disruption of the tumour suppressor gene Fus1. J Pathol 211:591-601

Yi Lo, Paulisally Hau; Chung Leung, Alfred Chi; Xiong, Wenjun et al. (2006) Expression of candidate chromosome 3p21.3 tumor suppressor genes and down-regulation of BLU in some esophageal squamous cell carcinomas. Cancer Lett 234:184-92

Miller, A D; Vigdorovich, V; Strong, R K et al. (2006) Hyal2, where are you? Osteoarthritis Cartilage 14:1315-7

Angeloni, Debora; ter Elst, Arja; Wei, Ming Hui et al. (2006) Analysis of a new homozygous deletion in the tumor suppressor region at 3p12.3 reveals two novel intronic noncoding RNA genes. Genes Chromosomes Cancer 45:676-91

Yau, Wing Lung; Lung, Hong Lok; Zabarovsky, Eugene R et al. (2006) Functional studies of the chromosome 3p21.3 candidate tumor suppressor gene BLU/ZMYND10 in nasopharyngeal carcinoma. Int J Cancer 119:2821-6

Kuzmin, Igor; Geil, Laura; Gibson, Lauren et al. (2005) Transcriptional regulator CTCF controls human interleukin 1 receptor-associated kinase 2 promoter. J Mol Biol 346:411-22

Li, Jingfeng; Wang, Fuli; Haraldson, Klas et al. (2004) Functional characterization of the candidate tumor suppressor gene NPRL2/G21 located in 3p21.3C. Cancer Res 64:6438-43

Ivanov, Sergey V; Ward, Jerrold M; Tessarollo, Lino et al. (2004) Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene. Am J Pathol 165:1007-18