Corepressor CtBP and Nuclear Speckle Protein Pnn/DRS Differentially Modulate Transcription and Splicing of the E-Cadherin Gene

Abstract

CtBP is a transcriptional corepressor with tumorigenic potential that targets the promoter of the tumor suppressor gene E-cadherin. Pnn/DRS (Pnn) is a "nuclear speckle"-associated protein involved in mRNA processing as well as transcriptional regulation of E-cadherin via its binding to CtBP. Here, we show that CtBP can recruit Pnn to CtBP-associated complexes, resulting in Pnn-dependent chromatin remodeling at the E-cadherin promoter. In addition, CtBP and Pnn can differentially modulate E-cadherin mRNA splicing, with polymerase II serving as an interface in this event. Therefore, the Pnn/CtBP functional interplay represents a novel mechanism linking the corepressor CtBP and Pnn to the transcription-coupled mRNA splicing of a major tumor suppressor gene. Our findings implicate the existence of the molecular switches involved in tumorigenesis, which coordinate promoter-specific events and mRNA processing, by serving as bridging elements between the regulatory complexes both at gene promoters and within the mRNA splicing machineries.

Pinin modulates expression of an intestinal homeobox gene, Cdx2, and plays an essential role for small intestinal morphogenesis

“…8F, G). These observations imply that, as previously shown in CDH1 promoter regulation (Alpatov et al, 2004; Alpatov et al, 2008), PNN and CtBP proteins are directly involved in the regulation of CDX2 promoter activity.…”

“…4G, Cdx2 was transcriptionally downregulated in Pnn-depleted small intestine. Since PNN was previously shown to relieve transcriptional repression activity of CtBPs and thus lead to the derepression of CDH1 ( E-Cadherin ) promoter (Alpatov et al, 2004; Alpatov et al, 2008), we examined whether PNN is directly involved in the promoter regulation of Cdx2 in two human cell lines, OE33 and EcR293 cells, both expressing GFP-tagged PNN protein. Semi-quantitative RT-PCR assay revealed that both OE33 and EcR293 cells express CDX2 , however neither of them expressed CDX1 (Fig.…”

“…The expression of Pnn has been shown to enhance cell-cell adhesion, inhibit cell migration, suppress tumorigenesis, transcriptionally regulate expression of E-cadherin ( CDH1 ) and p21 Waf1/Cip1 genes, and participate in alternative pre-mRNA splicing (Alpatov et al, 2004; Alpatov et al, 2008; Joo et al, 2005; Shi and Sugrue, 2000; Shi et al, 2000a; Shi et al, 2001; Shi et al, 2000b; Zimowska et al, 2003). Although the exact mechanism by which Pnn’s varied activities are translated into enhanced epithelial phenotype is currently unclear, we have recently demonstrated Pnn’s impact on Wnt/β-catenin signaling (Joo et al, 2010; Joo et al, 2007).…”

Pinin associates with prognosis of hepatocellular carcinoma through promoting cell proliferation and suppressing glucose deprivation-induced apoptosis

“…The biological functions of Pinin have been mainly discovered in epithelial cell behaviors as its participation in forming desmosome. Besides, its aberrant expression suppressed renal cancer development [14, 17]. …”

C-terminal binding proteins: central players in development and disease

“…The cell adhesion-related phoshoprotein, pinin/DRS (Pnn), has been shown to directly interact with CtBP1 and interfere with its ability to repress E-cadherin expression (137). CtBPs are also regulated at the post-transcriptional level by the miRNA degradation machinery.…”