We have cloned the ING family genes (p33ING2, p47ING3 and p29ING4). ING family genes have a PHD-finger motif, which is a C4HC3 zinc-finger-like motif found in nuclear proteins thought to be involved in chromatin-mediated transcriptional regulation. The function of this domain in not yet known, but in analogy with the LIM domain, it could be involved in protein-protein interaction and necessary for the assembly or activity of multicomponent complexes involved in transcriptional activation or repression. We have found that p33ING1, p33ING2 or p47ING3 inhibit cell growth and induce G1 cell cycle arrest in the wild-type p53 cancer cell line, RKO, but not in p53-deficient RKO cells transfected with HPV-E6. ING2 expression is induced by inhibitors of topoisomerase 1 and 2. In contrast, ING1 is not inducible by DNA damage and apparently is a housekeeping gene. Taken together, our results indicate that the ING gene family cooperates with p53 in the regulation of cell proliferation. Currently, we are investigating the role of these genes in apoptosis. We are conducting a positional cloning project to identity a putative tumor suppressor gene(s) on chromosomes 3p12.2 or 3q25.3, which are regions previously identified by allelic deletion and cytogenetic analysis, thought to harbor candidate tumor suppressor genes. Koji Sasajima, a former LHC fellow, has identified a colorectal cancer patient with diffuse digestive tract polyposis and a germline abnormality in chromosome 3;(3)(p12.2q25.3). Therefore, we proposed the hypothesis that the gene(s) affected by the chromosome inversion, predisposed the patient to diffuse polyposis and malignancy. The chromosomal 3 breakpoints of this patient have been isolated by positional cloning strategy. We and our collaborator microscopically dissected the chromosome fragments around the breakpoints. Using a DNA probe isolated from the dissected fragments, we made YAC contigs and YAC clones containing the breakpoint in 3p that were identified by FISH (fluorescent in situ hybridization). The cosmid contigs were made from these YACs, cosmid clones spanning the breakpoint were identified by FISH, and the nucleotide sequence at and around the breakpoint in both 3p12.2 and 3q25.3 were determined. The patient was found to have a 2bp deletion in 3p12.2 and about a 300kb deletion in 3q25.3. An extensive search for the gene(s) disrupted by the chromosome inversion is in progress by two ways: (1) determination of the nucleotide sequence around the breakpoints - 120 kb in 3p and 130 kb in 3q - have been determined; and (2) long-range exon trapping which is a recently developed procedure. The candidate transcribed sequences are to be studied by investigating their abnormalities in cancer cells. Thus far, we have obtained two clusters of possible transcribed sequences, both of which have significant homology with the EST(expressed sequence tag) clones of unknown function.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005795-06
Application #
6433067
Study Section
(LHC)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Solomon, Hilla; Dinowitz, Nathan; Pateras, Ioannis S et al. (2018) Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers. Oncogene 37:1669-1684
Cooks, Tomer; Harris, Curtis C (2014) p53 mutations and inflammation-associated cancer are linked through TNF signaling. Mol Cell 56:611-2
Kumamoto, Kensuke; Fujita, Kaori; Kurotani, Reiko et al. (2009) ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression. Int J Cancer 125:1306-15
Unoki, Motoko; Kumamoto, Kensuke; Robles, Ana I et al. (2008) A novel ING2 isoform, ING2b, synergizes with ING2a to prevent cell cycle arrest and apoptosis. FEBS Lett 582:3868-74
Kumamoto, Kensuke; Spillare, Elisa A; Fujita, Kaori et al. (2008) Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. Cancer Res 68:3193-203
Shen, Jiang-Cheng; Unoki, Motoko; Ythier, Damien et al. (2007) Inhibitor of growth 4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1. Cancer Res 67:2552-8
Yang, Qin; Zhang, Ran; Horikawa, Izumi et al. (2007) Functional diversity of human protection of telomeres 1 isoforms in telomere protection and cellular senescence. Cancer Res 67:11677-86
Hussain, S P; Schwank, J; Staib, F et al. (2007) TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene 26:2166-76
Koshiji, Minori; Kumamoto, Kensuke; Morimura, Keiichirou et al. (2007) Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity. World J Gastroenterol 13:2803-10
Okano, Tetsuya; Gemma, Akihiko; Hosoya, Yoko et al. (2006) Alterations in novel candidate tumor suppressor genes, ING1 and ING2 in human lung cancer. Oncol Rep 15:545-9

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