Altered Expression of Protein Tyrosine Phosphatase by Methylation

Ohio State University, Columbus OH

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Abstract

The receptor-type protein tyrosine phosphatase, PTPRO, is known to induce cell contact inhibition, cell cycle[unreadable] arrest, terminal cell differentiation and apoptosis in human cancer cell lines, particularly leukemia cells. Our[unreadable] study has shown that PTPRO is suppressed by hypermethylation in human primary tumors (hepatocellular,[unreadable] lung and CLL) as well as leukemia and lung cancer lines, and that ectopic expression of the full length form[unreadable] PTPRO-FL in non-expressing cells inhibited anchorage-independent growth, delayed re-entry of the cells into[unreadable] cell cycle, increased susceptibility to apoptosis and inhibited tumor growth in nude mice. Further, PTPRO is[unreadable] localized to chromosome 12p12.3 that is characterized by loss of heterozygosity in a variety of human cancer,[unreadable] a characteristic of many tumor suppressor genes. In addition, patients exhibiting PTPRO promoter[unreadable] methylation had higher expression of at least three anti-apoptotic proteins (Bcl2, Mcl-1, XIAP) independent of[unreadable] other commonly known prognostic factors including interphase cytogenetics, VH and p53 mutational status.[unreadable] The hypothesis of this project is that PTPRO has the potential for functioning as a growth/tumor suppressor[unreadable] that could be utilized as a novel molecular target in cancer, particularly CLL, therapy. The specific aims are to[unreadable] ( 1) Investigate whether PTPROt (predominant form in cells of lymphoid origin) expression is down-regulated[unreadable] in chronic lymphocytic leukemia (CLL), whether PTPRO promoter methylation identifies a subset of high risk[unreadable] group of CLL patients, and whether the suppression of PTPROt correlates inversely with the methylation[unreadable] status/density of the CpG island located in the promoter (2) confirm the growth/tumor suppressor property or[unreadable] anti-transformation potential and pro-apoptotic property of PTPROt isoforms, (3) identify the substrate(s) of[unreadable] the PTPROt isoforms and (4) elucidate the molecular mechanism by which methylation suppressed[unreadable] expression of PTPRO by (a) exploring the chromatin structure of PTPRO promoter (b) investigating whether[unreadable] the novel post-translational modifications of core histones (identified in Project 4) are associated with the[unreadable] PTPRO promoter in normal B lymphocytes and whether this association is altered in CLL(c) determining the[unreadable] involvement of DNA methyltransferases, methyl CpG binding proteins, and chromatin remodelers (studied in[unreadable] Project 5) in regulating PTPRO expression in CLL cells. Project 1 will interact with this project in studies on[unreadable] re-activation of the suppressed genes by agents that inhibit DNA methyltransferases and histone[unreadable] deacetylases. It is hoped that this study will provide a novel molecular target in CLL therapy and molecular[unreadable] marker for CLL, and could reveal the potential for drug resistance in a subset of CLL patients with PTPRO[unreadable] methylation independent of other commonly known prognostic markers.