C-terminal binding proteins: Emerging roles in cell survival and tumorigenesis

Bergman, Lee; Blaydes, Jeremy P.

doi:10.1007/s10495-006-6651-4

Cited by 56 publications

(62 citation statements)

References 108 publications

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“…Several pathways regulate CtBP-mediated repression via effects on dimerization, nuclear localization, or degradation. Notably, oxidative stress, UV exposure, and wound healing, which are associated with increased p16 expression (1, 7), involve pathways that relieve CtBP-mediated repression (5,6). Our results document the role of CtBP in the control of p16 and indicate how CtBP-mediated repression could contribute to the silencing of p16 in the hypoxic environment typical of solid tumors (8).…”

Section: Introductionmentioning

confidence: 52%

“…Few mechanisms that regulate p16 separately from the alternate product of the CDKN2A gene, p14 ARF , are known. Our comparison of the oncoproteins adenoviral E1A and the large T antigen of SV40 pointed us to a previously unsuspected component of upstream p16 control-COOH-terminal binding protein (CtBP), a physiologically regulated corepressor (5,6). CtBP dimers form bridges between proteins having PxDLS amino acid motifs, including several transcription factors and other proteins involved in the regulation of transcription, including CtIP and components of Polycomb complexes.…”

Section: Introductionmentioning

confidence: 99%

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COOH-Terminal Binding Protein Regulates Expression of the p16INK4A Tumor Suppressor and Senescence in Primary Human Cells

et al. 2008

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Section: Introductionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

COOH-Terminal Binding Protein Regulates Expression of the p16INK4A Tumor Suppressor and Senescence in Primary Human Cells

et al. 2008

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“…Some reports have also suggested that CtBPs can mediate an epithelial-mesenchymal transition (22,26). The structure of CtBPs make them well suited to respond to environmental cues that alter cell metabolism, such as hypoxia, as they encode a vestigial dehydrogenase that senses the NADH/NAD + ratio in cells, with increased NADH causing upregulation of corepressor function (27). In this report, NADH binding was required for CtBP2-induced cell migration whether in normoxia or hypoxia, likely reflecting the loss of NADH-dependent corepressor activity induced by this mutation (28).…”

Section: Discussionmentioning

confidence: 99%

The Alternative Reading Frame Tumor Suppressor Antagonizes Hypoxia-Induced Cancer Cell Migration via Interaction with the COOH-Terminal Binding Protein Corepressor

Paliwal¹,

Kovi²,

Nath³

et al. 2007

Cancer Research

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The alternative reading frame (ARF) tumor suppressor exerts both p53-dependent and p53-independent activities critical to the prevention of cancer in mice and humans. Recent evidence from mouse models suggests that when p53 is absent, further loss of ARF can widen the tumor spectrum, and potentiate invasion and metastasis. A major target of the p53-independent activity of ARF is the COOH-terminal binding protein (CtBP) family of metabolically regulated transcriptional corepressors, which are degraded upon acute exposure to the ARF protein. CtBPs are activated under conditions of metabolic stress, such as hypoxia, to repress epithelial and proapoptotic genes, and can mediate hypoxia-induced migration of cancer cells. The possibility that ARF could suppress tumor cell migration as part of its p53-independent activities was thus explored. Small-interfering RNA (siRNA)-mediated knockdown of ARF in human lung carcinoma cells led to increased cell migration, especially during hypoxia, and this effect was blocked by concomitant treatment with CtBP2 siRNA. Introduction of ARF into p53 and ARF-null human colon cancer cells inhibited hypoxia-induced migration. Furthermore, overexpression of CtBP2 in ARF-expressing cells enhanced cell migration, and an ARF mutant defective in CtBP-family binding was impaired in its ability to inhibit cell migration induced by CtBP2. ARF depletion or CtBP2 overexpression was associated with decreased PTEN expression and activation of the phosphatidylinositol 3-kinase pathway, and a phosphatidylinositol 3-kinase inhibitor blocked CtBP2-mediated cell migration. Thus, ARF can suppress cell migration by antagonizing CtBP2 and the phosphatidylinositol 3-kinase pathway, and these data may explain the increased aggressiveness of ARF-null tumors in mouse models.

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“…In the current study, we demonstrated a novel role for the C-terminal binding protein 1 (CtBP1), a transcriptional co-regulator that favors oncogenesis and tumor cell survival (11), in the activation of MDR1 expression. CtBP1, a 48 kDa protein that was originally shown to bind to the C-terminal region of the human adenovirus E1A proteins (12), is present in both the nucleus and cytoplasm, and functions mainly as a transcriptional corepressor (13).…”

Section: Introductionmentioning

confidence: 89%

Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells

Jin

Scotto

Hait

et al. 2007

Biochemical Pharmacology

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Drug resistance caused by overexpression of P-glycoprotein (P-gp), the MDR1 (ABCB1) gene product, limits the therapeutic outcome. Expression of MDR1 can be induced by divergent stimuli, and involves a number of transcriptional factors. We found that the expression of CtBP1 (C-terminalbinding protein 1), a transcriptional co-regulator, was increased (~4 -fold) in human multidrug resistant (MDR) cancer cell lines, NCI/ADR-RES and A2780/DX, as compared to their sensitive counterparts. Silencing of CtBP1 expression by RNAi decreased the MDR1 mRNA and P-gp. Knockdown of CtBP1 also enhanced the sensitivity of MDR cells to chemotherapeutic drugs that are transported by P-gp and increased intracellular drug accumulation. In a reporter gene assay, cotransfection of MDR1 promoter constructs with a CtBP1 expression vector resulted in a ~2-4-fold induction of MDR1 promoter activity. CtBP1 appeared to contribute to the activation of MDR1 transcription through directly interacting with the MDR1 promoter, as evidenced by its physical binding to the promoter region of the MDR1 gene in chromatin immunoprecipitation and electromobility shift assays. Histone modifications at the MDR1 promoter, such as monomethylation, di-methylation, and acetylation of histone H3, were not found to be affected by silencing of CtBP1 expression. Our results reveal a novel role for CtBP1 as an activator of MDR1 gene transcription, and suggest that CtBP1 might be one of the key transcription factors involved in the induction of MDR1 gene. Therefore, CtBP1 may represent a potentially new target for inhibiting drug resistance mediated by overexpression of the MDR1 gene.

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C-terminal binding proteins: Emerging roles in cell survival and tumorigenesis

Cited by 56 publications

References 108 publications

COOH-Terminal Binding Protein Regulates Expression of the p16INK4A Tumor Suppressor and Senescence in Primary Human Cells

COOH-Terminal Binding Protein Regulates Expression of the p16INK4A Tumor Suppressor and Senescence in Primary Human Cells

The Alternative Reading Frame Tumor Suppressor Antagonizes Hypoxia-Induced Cancer Cell Migration via Interaction with the COOH-Terminal Binding Protein Corepressor

Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells

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