This is a new proposal to identify and study the function of a putative recessive tumor suppressor gene or genes in 3p21.3 important in the development of lung cancers. Evidence for such a tumor suppressor comes from studies showing the early loss of 3p21 alleles in preneoplasia, and allele loss of 3p genes in 70-80% of both small cell and non-small cell lung cancers.
In specific aim I it is proposed to clone the gene using a series of resources including a set of homozygous deletions in lung tumor cell lines defining a 350 kb and potentially 30 kb critical region, and a high resolution physical and transcription map with 25 cDNA clones already identified in this region.
Specific aim 2 is to determine functional characteristics of this locus by introduction of portions of chromosome 3p into human lung cancer lines bearing a 3p21.3 abnormality, and testing for suppression of tumorigenicity using nude mice, soft agarose culture and studies of apoptosis.
In specific aim 3 the applicant plans to follow up on an observation that this region might be involved in suppressing telomerase activity by investigating telomere length and telomerase function in lung cancer cells altered by gene transfer.
|Gao, Boning; Xie, Xian-Jin; Huang, Chunxian et al. (2008) RASSF1A polymorphism A133S is associated with early onset breast cancer in BRCA1/2 mutation carriers. Cancer Res 68:22-5|
|Castro-Rivera, Emely; Ran, Sophia; Brekken, Rolf A et al. (2008) Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells. Cancer Res 68:8295-303|
|Whitehurst, Angelique W; Ram, Rosalyn; Shivakumar, Latha et al. (2008) The RASSF1A tumor suppressor restrains anaphase-promoting complex/cyclosome activity during the G1/S phase transition to promote cell cycle progression in human epithelial cells. Mol Cell Biol 28:3190-7|
|Ohtani, Shoichiro; Iwamaru, Arifumi; Deng, Wuguo et al. (2007) Tumor suppressor 101F6 and ascorbate synergistically and selectively inhibit non-small cell lung cancer growth by caspase-independent apoptosis and autophagy. Cancer Res 67:6293-303|
|Deng, Wu-Guo; Kawashima, Hiroyaki; Wu, Guanglin et al. (2007) Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer cells. Cancer Res 67:709-17|
|Jayachandran, Gitanjali; Sazaki, Ji-ichiro; Nishizaki, Masahito et al. (2007) Fragile histidine triad-mediated tumor suppression of lung cancer by targeting multiple components of the Ras/Rho GTPase molecular switch. Cancer Res 67:10379-88|
|Sato, Mitsuo; Vaughan, Melville B; Girard, Luc et al. (2006) Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells. Cancer Res 66:2116-28|
|Moshnikova, Anna; Frye, Judson; Shay, Jerry W et al. (2006) The growth and tumor suppressor NORE1A is a cytoskeletal protein that suppresses growth by inhibition of the ERK pathway. J Biol Chem 281:8143-52|
|Ueda, Kentaro; Kawashima, Hiroyuki; Ohtani, Shoichiro et al. (2006) The 3p21.3 tumor suppressor NPRL2 plays an important role in cisplatin-induced resistance in human non-small-cell lung cancer cells. Cancer Res 66:9682-90|
|Kim, Y H; Girard, L; Giacomini, C P et al. (2006) Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification. Oncogene 25:130-8|
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