hallmark of human cancer, particularly solid tumor, is genomic instability. Through a synthetic lethal screen with the Ras oncogene we have found that Ras mutant cancer cells exhibit increased mitotic stress and are more dependent on the proper function of a subset of mitotic genes to avoid gross chromosomal mis-segregation and cell death.PURPOSETo study the effect of Ras mutation in mitosis and in chromosomal segregation. To understand the mechanisms by which mutant Ras affects the mitotic machinery.SIGNIFICANT MATERIALS AND METHODSWe use KRAS WT and mutant isogenic cell lines as well as colorectal cancer (CRC) cell lines that are either dependent or independent of KRAS to investigate their response to perturbation of mitotic progression. FY2012 ACCOMPLISHMENTIn 2011 identified a novel gene ERH (enhancer of rudimentary) that shows synthetic lethality with Ras mutation and is required for chromosome congression in mitosis. We discovered that ERH is required for the expression of a number of mitotic genes. In particular ERH is required for the expression of the mitotic motor protein CENP-E. Depletion of ERH results in loss of CENP-E mRNA. Using SILAC mass-spectrometry, we discovered that ERH binds to the splicing factor and Sm protein SNRPD3 and is required for the splicing of CENP-E mRNA. These findings established the role of ERH as an mRNA splicing factor that is required for the expression of a subset of cell cycle genes. Clinically the expression of ERH is associated with aggressive colorectal cancer (CRC) and poor prognosis in CRC patients with KRAS mutations. Our manuscript on this study has been submitted.
|Maity, Tapan K; Venugopalan, Abhilash; Linnoila, Ilona et al. (2015) Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor-Driven Lung Adenocarcinoma. Cancer Discov 5:534-49|
|Weng, Meng-Tzu; Lee, Jih-Hsiang; Wei, Shu-Chen et al. (2012) Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells. Proc Natl Acad Sci U S A 109:E3659-67|