The CtBP family: enigmatic and enzymatic transcriptional co‐repressors

Abstract

Transcription factors that associate with DNA sequences in promoters and enhancers often recruit co-regulators that modulate their activity. Many of these co-regulators have intrinsic enzymatic activity and influence gene expression by modifying chromatin and altering its structure. Recently, a new family of co-repressors, the C-terminal binding proteins, has been described. These proteins recognize Pro-X-Asp-Leu-Ser (PXDLS) motifs in DNA-binding proteins and function as transcriptional co-repressors in Drosophila, Xenopus and mammals. The precise mechanisms by which they influence transcription are still under investigation. CtBP proteins dimerize and can contact histone deacetylases; hence they may operate by linking deacetylases to DNA-bound factors. But it appears that CtBP proteins also have intrinsic enzymatic activity. They have significant homology to D-isomer-specific 2-hydroxy acid dehydrogenases, and remarkably one family member, rat CtBP, has been shown to have a second role, functioning as an acyl transferase in Golgi maintenance. These observations raise the possibility that CtBP proteins might regulate gene expression directly by means of their enzymatic activities, in addition to serving as simple bridging proteins. Supplementary material for this article can be found on the BioEssays homepage at http://www.interscience.wiley.com/jpages/0265-9247/suppmat/v23_8.684.

Interaction between Smad-interacting Protein-1 and the Corepressor C-terminal Binding Protein Is Dispensable for Transcriptional Repression of E-cadherin

“…Histone deacetylases as well as Polycomb proteins can induce modifications of the nucleosomal organization (14,15). We considered the possibility that our inability to show a CtBP-dependent repression of the E-cadherin promoter by SIP1 could be due to the use of reporter plasmids.…”

“…In the case of the E-cadherin promoter and its regulation by ␦EF1, the corepressor C-terminal binding protein (CtBP) was proposed to be necessary for transcriptional repression (10). CtBP was originally identified as a protein that interacts with the C-terminal segment of the adenovirus E1A oncoprotein via a PLDLS sequence in the latter (13), and interacts with a growing list of transcription factors from Drosophila and vertebrates (14,15). Two highly related CtBP proteins, CtBP1 and CtBP2, have been identified in vertebrates and have overlapping but also unique roles during embryogenesis, as shown by loss-of-function studies in the mouse (16).…”

Quantitative contributions of CtBP-dependent and -independent repression activities of Knirps

“…Although not identified in previous studies, recent reports found a weak dehydrogenase activity associated with CtBP (Kumar et al, 2002;Balasubramanian et al, 2003;Shi et al, 2003). CtBP has been found to bind directly to histone deacetylases (HDACs), suggesting that the corepressor may effect repression by chromatin remodeling (reviewed by Turner and Crossley, 2001;Chinnadurai, 2002). A recent biochemical purification of CtBP identified additional proteins in a complex, including histone methyltransferases, the CoREST repressor and a protein homologous to polyamine oxidases (Shi et al, 2003).…”

“…Transcription factors typically bind to CtBP via a short peptide motif similar to the PLDLS sequence originally identified in E1A (Schaeper et al, 1995). CtBP is homologous to α-hydroxyacid dehydrogenases, and contains a conserved NADbinding domain as well as conserved residues in the putative active site (reviewed by Chinnadurai, 2002;Turner and Crossley, 2001). Although not identified in previous studies, recent reports found a weak dehydrogenase activity associated with CtBP (Kumar et al, 2002;Balasubramanian et al, 2003;Shi et al, 2003).…”

C-terminal-binding protein interacting protein binds directly to adenovirus early region 1A through its N-terminal region and conserved region 3

“…Deletion of the C-terminal region of AdE1A reduces the frequency of transformation by AdE1A together with AdE1B, but increases the frequency of transformation by AdE1A and activated ras (Douglas et al, 1991;Subramanian et al, 1989Subramanian et al, , 1991. CtBP has been shown to interact with a large number of mammalian transcriptional repressors, such as BKLF, Ikaros, Net and the Drosophila repressors Snail, Hairy and Knirps as well as histone deacetylases (HDACs) (reviewed by Turner and Crossley, 2001;Chinnadurai, 2002Chinnadurai, , 2004Chinnadurai, , 2006aChinnadurai, , 2007.…”