The retinoblastoma gene family consisting of RB/p105, p107, and RB2/p130 cooperate to regulate cell-cycle progression through the G1 phase of the cell cycle. Previous data demonstrated an independent role for the reduction or loss of pRb2/p130 expression in the formation and/or progression of lung carcinoma. Rb2/p130 is mutated in a human cell line of lung small cell carcinoma as well as in primary lung tumors. To identify potential pRb2/p130 target genes in an unbiased manner, we have utilized an adenovirus-mediated expression system of pRb2/p130 in a non-small lung cancer cell line to identify specific genes that are regulated by pRb2/p130. Using oligonucleotide arrays, a number of Rb2/p130 downregulated genes were identified and their regulation was confirmed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. As a result, 40 genes showed greater than 2.0-fold modification in their expression level after the RB2/p130 viral transduction. In conclusion, coupling adenoviral overexpression with microarray and semiquantitative RT-PCR analyses proved to be a versatile strategy for identifying pRb2/p130 target genes and for better understanding the expression profiles of these genes. Our results may also contribute to identifying novel therapeutic biomarkers in lung carcinoma.
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University of North Carolina School of Medicine, Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, 515 Brinkhous-Bullitt Building, CB# 7525, Chapel Hill, NC 27599, USA +1 919 966 2699 ; +1 919 966 5046 ;
This application claims: i) a method for detecting cancer cells based on analysis of gene mutations and/or promoter methylation of the pRb2/p130 gene; ii) a method for diagnosing cancer based on analysis of gene mutations and/or promoter methylation of the pRb2/p130 gene; iii) a method for detection of cells that are predisposed to tumorigenesis based on analysis of gene mutations and/or promoter methylation of the pRb2/p130 gene; iv) a method for treating cancer and/or inhibiting tumorigenesis based on demethylation of the pRb2/p130 gene promoter; and v) a method for treating cancer and/or inhibiting tumorigenesis based on inhibition of other proteins that interact with or regulate pRb2/p130. This application is founded on the recognition that: i) pRb2/p130 is a frequent target of genetic or epigenetic alteration in various human cancers; ii) the resulting loss of regulation of cell cycle progression contributes to the phenotypic characteristics of these neoplasms; iii) pRb2/p130 represents a valuable biomarker for detection/diagnosis of some cancers; and iv) pRb2/p130 may be a useful gene target for development of new cancer therapeutics.
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