In promoting sister chromatid cohesion in S. cerevisiae (54). As sister chromatid cohesion limits recombination amongst homologous chromosomes (55), disrupting sister chromatid cohesion by way of such mutations could facilitate enhanced levels of interchromosomal GC. We have identified roles for the DNA harm checkpoint pathway, including homologues of the haploinsufficient tumor suppressors, Rad3ATR , Crb253BP1 and Chkin suppressing break-induced LOH (568). Our data recommend that these homologues may possibly function to suppress tumorigenesis via promoting efficient HR thereby suppressing extensive resection, chromosomal rearrangements and extensive LOH. Moreover, we found that overexpression of Cdc25, which abrogates the DNA harm checkpoint, resulted in inefficient HR repair, increased levels of break-induced chromosome loss and LOH. Reduced HR efficiency following Cdc25 overexpression may have arisen from inappropriate cyclin-dependent kinase (CDK) dependent activation of CtIP and hence extensive resection, as recommended from research in S. cerevisiae (59), or alternatively through a lowered G2-phase and accelerated entry into mitosis by means of enhanced CDK activity. In humans, CDC25 orthologues can function as oncogenes and are regularly over expressed in high-grade tumours with poor prognosis (reviewed in (60)). Our findings recommend a mechanistic explanation for these observations. SUPPLEMENTARY Data Supplementary Information are obtainable at NAR Online. ACKNOWLEDGEMENT We thank the laboratory of Antony Carr for strains and reagents. FUNDING Medical Research Council [R06538 to H.T.P., E.B., T.K., L.H., S.H., R.Tralokinumab D., C.W., C.P., T.H.]; Cancer Analysis UK [C9546/A6517 to S.M., J.B.]; A*STAR, Singapore (to B.W.); Grant-in-Aid for Scientific Investigation from the Japan Society for the Promotion of Science (to T.N.). Source of open access funding: MRC (T.H.). Conflict of interest. None declared.
OPENCitation: Oncogenesis (2013) two, e59; doi:10.1038/oncsis.2013.17 2013 Macmillan Publishers Restricted All rights reserved 2157-9024/13 www.nature/oncsisORIGINAL ARTICLEPeriostin cooperates with mutant p53 to mediate invasion by means of the induction of STAT1 signaling within the esophageal tumor microenvironmentGS Wong1,2,3, J-S Lee4, Y-Y Park4, AJ Klein-Szanto5, TJ Waldron1,2,three, E Cukierman5, M Herlyn6, P Gimotty3,7, H Nakagawa1,2,3 and AK Rustgi1,two,3,eight Periostin (POSTN), a matricellular protein, has been reported to be crucial in supporting tumor cell dissemination.Bazedoxifene However, the molecular mechanisms underlying POSTN function inside the tumor microenvironment are poorly understood.PMID:23439434 Within this study, we observe that the inducible knockdown of POSTN decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that POSTN cooperates with a conformational missense p53 mutation to improve invasion. Pathway analyses reveal that invasive esophageal cells expressing POSTN and p53R175H mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells in to the extracellular matrix. Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the value of STAT1 in promoting invasion. In addition, we find that STAT1 is activated in ESCC xenograft tumors, but this activation is attenuated with inducible knockdown of POSTN in ESCC.