Osphorylated on Ser422 or Ser 428 (CtBP1 or CtBP2, respectively) by either homeodomain interacting protein kinase-2 or c-Jun NH2-terminal kinase, targeting these proteins for subsequent ubiquitinylation and proteasomal degradation (Zhang et al., 2003; Zhang et al., 2005; Wang et al., 2006). Beneath some circumstances, targeting of CtBP for the proteasome may perhaps require interaction with more proteins like the tumor suppressor ARF (Paliwal et al., 2006). Recently, additional pathways have already been recommended to regulate CtBP expression by way of the proteasome. As an illustration, AKT1 has not too long ago been shown to cooperate together with the SUMO E3 ligase Pc2 to induce phosphorylation and ubiquitinylation of CtBP resulting in its enhanced degradation (Merrill et al., 2010). One more pathway for CtBP degradation includes its interaction together with the X-linked inhibitor of apoptosis protein which directly ubiquitinylates CtBP and targets it for proteasomal degradation (Lee et al., 2012). However, B-cell lymphoma-3 (Bcl-3) is often a proto-oncogene which has not too long ago been shown to interact with and stabilize CtBP by preventing its ubiquitinylation and subsequent proteasomal degradation (Choi et al., 2010). Interestingly, CtBP1 protein levels have been downregulated in HEK293T cells incubated with the apoptosis inducer etoposide, but this impact was prevented by overexpression of Bcl-3. Thus, proteasome-dependent degradation seems to become a dominant pathway for turnover of CtBPs in non-neuronal cells undergoing apoptosis. In marked contrast to these preceding studies, we have identified a novel caspase-dependent pathway for CtBP downregulation in neurons undergoing apoptosis. Regardless of the presence of a conserved caspase-3 consensus cleavage internet site within the CtBP1 and CtBP2 proteins, CtBPs doNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptMol Cell Neurosci. Author manuscript; accessible in PMC 2014 September 01.Stankiewicz et al.Pagenot appear to be direct caspase-3 substrates in vitro. Although it can not be ruled out that other caspase members of the family may directly cleave CtBPs in neurons undergoing apoptosis, the price of degradation of CtBP1 in CGNs is just not significantly altered in 5K (apoptotic) medium suggesting that the downregulation of CtBPs observed beneath these circumstances is not resulting from enhanced proteolysis. Intriguingly, CtBP1 and CtBP2 mRNA transcripts are usually not significantly decreased in CGNs subjected to 5K apoptotic conditions indicating that the downregulation of CtBPs likely occurs through a post-transcriptional mechanism.7-Bromo-1H-pyrazolo[3,4-c]pyridine site Consistent with this thought, the caspase-dependent downregulation of CtBP1 observed in mESCs exposed to staurosporine doesn’t happen in DGCR8 KO cells which are deficient in miRNA biogenesis.(S,R,S)-AHPC-amido-C5-acid site Collectively, these information recommend that the caspase-dependent downregulation of CtBPs observed in neurons undergoing apoptosis may well take place by way of a miRNA-dependent mechanism.PMID:24211511 Many current research add assistance towards the hypothesis that CtBPs are subject to considerable post-transcriptional regulation by miRNAs. As an illustration, the expression of miR-137 was discovered to inversely correlate with CtBP1 expression in melanoma cell lines. Furthermore, miR-137 suppressed CtBP1 3′ UTR luciferase-reporter activity and overexpression of miR-137 decreased CtBP1 levels and triggered a corresponding boost in expression in the CtBP1 target Bax (Deng et al., 2011). Interestingly, the miR-137 gene is discovered on chromosome 1p22 that is a identified susceptibility area for melanoma and furth.