In order to identify the lowest efficacious dose of PA 824 for the treatment of

miR 145 is expressed at a low level and then is elevated in differentiated epithelial cells and becomes downregulated again in neoplastic cells. However, the underlying mechanism of miR 145 regulation, especially Cabozantinib in cancer, is elusive. We present evidence that C/EBP b is a negative regulator of miR 145 which may be in part responsible for downregulation of miR 145 in tumor cells. As a transcriptional repressor, C/EBP b has been shown to transcriptionally repress a variety of genes including let 7i. Thus, identification of C/EBP b as a negative regulator of miR 145 expands the growing list of C/EBP b regulated genes. More importantly, we show that phosphorylation of C/EBP b is critical to this negative effect on miR 145. In this regard, we identify Akt as a potential upstream regulator of CEBP b, as supported by several lines of evidence. First, activation of Akt correlates with phosphorylation of C/EBP b, second, this positive Retroperitoneal lymph node dissection correlation has been previously reported in clinical specimens and third, RSV induces miR 145 and at the same time, it decreases pAkt as well as phosphorylation of C/EBP b. Therefore, these suggest a possible pathway leading to miR 145 induction through C/EBP b. The ability of C/EBP b to suppress miR 145 appears to function through counteraction of the ability of p53 to induce miR 145 in the wild type p53 background. We show that p53 increases the endogenous miR 145 level as well as the miR 145 promoter activity, on the other hand, ectopic expression of C/EBP b suppressed the p53 mediated induction of miR 145 and the miR 145 promoter activity. It is known that p53 interacts with C/EBP b, and such interaction is functional because C/EBP b has been shown to represses AG-1478 p53 to promote cell survival or subsequently suppress p53 downstream genes. Thus, our study provides further evidence that miR 145 is under the control of a complex regulatory system involving p53 and C/EBP b. The dysregulation of p53 C/EBP b cross talk is expected to play an important role in tumorigenesis. For example, enhanced expression of C/EBP b may antagonize the tumor suppressive role of p53. On the other hand, an increased level of p53 would keep the tumor promoting role of C/EBP b in check. It remains to be determined regarding the mechanism by which C/EBP b can suppress miR 145 in the mutant p53 background. One possibility is that C/EBP b may act alone or counteract with other unknown activator to suppress miR 145 expression. In support of this possibility, it has been shown that C/EBP b itself can play a repressive role, and thus, we expect that increased levels of C/EBP b would suppress its targeted genes such as miR 145, because C/EBP b is frequently upregulated in cancer cells. Although three isoforms of C/EBP b might be formed, the cell lines we tested only express LAP 2 and/or LIP.