The long term goals of this program are to identify new genes whose loss or inactivation allows a cell to display one or another phenotype of neoplastic growth deregulation, to characterize their cellular function and cancer relevance. The program is based on the use of the genetic suppressor element (GSE) methodology that was specifically designed for this study. During the first phase of this program (1994 through1998) a large set of transforming GSEs were isolated, and two GSE corresponding genes were characterized in detail. ING1 gene was defined as a new modulator of p53 signaling pathway and the kinesin motor protein was shown to mediate drug sensitivity and senescence. The major goals of the next phase of this program include functional analysis of the genes identified during the first stage of the study, with the main focus on ING1, and the development of a new powerful version of the GSE methodology. ING1 gene was found to encode two proteins that have opposite effect on p53 function. Biological functions and cancer relevance of ING1 gene will be analyzed in vitro and in vivo in transgenic and knockout mice (Aim 1). A hypothesis will be explored that unbalanced expression of ING1 proteins could contribute to the inactivation of p53 pathway in tumors. The mechanism of functional interaction between p53 and ING1 will be characterized in a series of biochemical studies that will involve identification of ING1 cellular counterparts (Aim 2). The GSE methodology will be upgraded by developing a novel approach to isolation of GSEs cooperating in vitro or in vivo with activated oncogenes in cell transformation (Aim 3). A new procedure of efficient GSE processing and classification involving preparation of GSE hybridization arrays will be developed and applied to characterization of previously and newly isolated GSEs and GSE corresponding genes. GSE database will be created and made available to biomedical researchers in the form of DNA hybridization arrays.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA060730-09
Application #
6512974
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Mietz, Judy
Project Start
1994-01-03
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
9
Fiscal Year
2002
Total Cost
$266,400
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Neznanov, Nickolay; Komarov, Andrei P; Neznanova, Lubov et al. (2011) Proteotoxic stress targeted therapy (PSTT): induction of protein misfolding enhances the antitumor effect of the proteasome inhibitor bortezomib. Oncotarget 2:209-21
Lu, Tao; Jackson, Mark W; Wang, Benlian et al. (2010) Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A 107:46-51
Demidenko, Zoya N; Korotchkina, Lioubov G; Gudkov, Andrei V et al. (2010) Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci U S A 107:9660-4
Neznanov, Nickolay; Gorbachev, Anton V; Neznanova, Lubov et al. (2009) Anti-malaria drug blocks proteotoxic stress response: anti-cancer implications. Cell Cycle 8:3960-70
Lu, Tao; Jackson, Mark W; Singhi, Aatur D et al. (2009) Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NFkappaB. Proc Natl Acad Sci U S A 106:16339-44
Neznanov, Nickolay; Dragunsky, Eugenia M; Chumakov, Konstantin M et al. (2008) Different effect of proteasome inhibition on vesicular stomatitis virus and poliovirus replication. PLoS One 3:e1887
Komarov, Andrei P; Rokhlin, Oskar W; Yu, Chang-An et al. (2008) Functional genetic screening reveals the role of mitochondrial cytochrome b as a mediator of FAS-induced apoptosis. Proc Natl Acad Sci U S A 105:14453-8
Logunov, D Y; Scheblyakov, D V; Zubkova, O V et al. (2008) Mycoplasma infection suppresses p53, activates NF-kappaB and cooperates with oncogenic Ras in rodent fibroblast transformation. Oncogene 27:4521-31
Neznanov, Nickolay; Kondratova, Anna; Chumakov, Konstantin M et al. (2008) Quercetinase pirin makes poliovirus replication resistant to flavonoid quercetin. DNA Cell Biol 27:191-8
Xue, Chengyuan; Haber, Michelle; Flemming, Claudia et al. (2007) p53 determines multidrug sensitivity of childhood neuroblastoma. Cancer Res 67:10351-60

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