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

Jin, Wei; Scotto, Kathleen W.; Hait, William N.; Yang, Jin Ming

doi:10.1016/j.bcp.2007.06.017

Cited by 53 publications

(51 citation statements)

References 26 publications

(31 reference statements)

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“…A diminution in estrogen-stimulated gene expression in the absence of CtBP1 was also observed on two of three other estrogenstimulated genes tested. Although these results were unexpected, they are consistent with other findings that knockdown of CtBP1 led to reduced expression of the ATP binding cassette, subfamily B (MDR/TAP) member 1 (MDR1) gene (49).…”

Section: Discussionsupporting

confidence: 91%

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

Palijan

Fernandes

Verway

et al. 2009

Journal of Biological Chemistry

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Ligand-dependent corepressor LCoR interacts with the progesterone receptor (PR) and estrogen receptor ER␣ in the presence of hormone. LCoR contains tandem N-terminal PXDLS motifs that recruit C-terminal-binding protein (CtBP) corepressors as well as a C-terminal helix-turn-helix (HTH) domain. Here, we analyzed the function of these domains in coregulation of PR-and ER␣-regulated gene expression. LCoR and CtBP1 colocalize in nuclear bodies that also contain CtBP-interacting protein CtIP and polycomb group repressor complex marker BMI1. Coexpression of CtBP1 in MCF7 or T47D breast cancer cells augmented corepression by LCoR, whereas coexpression of CtIP did not, consistent with direct interaction of LCoR with CtBP1, but not CtIP. The N-terminal region containing the PXDLS motifs is necessary and sufficient for CTBP1 recruitment and essential for full corepression. However, LCoR function was also strongly dependent on the helix-turn-helix domain, as its deletion completely abolished corepression. LCoR, CtBP, and CtIP were recruited to endogenous PR-and ER␣-stimulated genes in a hormone-dependent manner. Similarly, LCoR was recruited to estrogen-repressed genes, whereas hormone treatment reduced CtBP1 binding. Small interfering RNA-mediated knockdown of LCoR or CtBP1 augmented expression of progesterone-and estrogen-stimulated reporter genes as well as endogenous progesterone-stimulated target genes. In contrast, their ablation had gene-specific effects on ER␣-regulated transcription that generally led to reduced gene expression. Taken together, these results show that multiple domains contribute to LCoR function. They also reveal a role for LCoR and CtBP1 as attenuators of progesterone-regulated transcription but suggest that LCoR and CtBP1 can act to enhance transcription of some genes.

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Section: Discussionsupporting

confidence: 91%

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

Palijan

Fernandes

Verway

et al. 2009

Journal of Biological Chemistry

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“…RCOR1 and CTBP1/2 have known roles in transcriptional repression in a complex with KDM1A (Shi et al 2003;Lee et al 2005). Roles for RCOR1 and CTBP1/2 in transcriptional activation have also been described, but the mechanism is not well understood (Fang et al 2006;Jin et al 2007;Abrajano et al 2010;Paliwal et al 2012). Transcriptional activation or repression by RCOR1 and CTBP1/2 likely depends on the specific transcription factors and chromatin regulators with which they are associated, as shown here.…”

Section: Discussionmentioning

confidence: 70%

ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes

et al. 2014

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ZNF750 controls epithelial homeostasis by inhibiting progenitor genes while inducing differentiation genes, a role underscored by pathogenic ZNF750 mutations in cancer and psoriasis. How ZNF750 accomplishes these dual gene regulatory impacts is unknown. Here, we characterized ZNF750 as a transcription factor that binds both the progenitor and differentiation genes that it controls at a CCNNAGGC DNA motif. ZNF750 interacts with the pluripotency transcription factor KLF4 and chromatin regulators RCOR1, KDM1A, and CTBP1/2 through conserved PLNLS sequences. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) and gene depletion revealed that KLF4 colocalizes~10 base pairs from ZNF750 at differentiation target genes to facilitate their activation but is unnecessary for ZNF750-mediated progenitor gene repression. In contrast, KDM1A colocalizes with ZNF750 at progenitor genes and facilitates their repression but is unnecessary for ZNF750-driven differentiation. ZNF750 thus controls differentiation in concert with RCOR1 and CTBP1/2 by acting with either KDM1A to repress progenitor genes or KLF4 to induce differentiation genes.

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“…Tiam1 is therefore a novel target for CtBP2 transcriptional regulation, but unlike its previously well-understood co-repression role, CtBP2 here is playing a paradoxical but previously described role as a transcription activator. [34][35][36][37][38] Notably, in H1299 cells but not HCT116 cells, the changes in the Tiam1 protein were consistently greater (positive or negative) than the changes in mRNA expression, suggesting that in these cells, additional posttranscriptional mechanisms may also be at play in the CtBP regulation of Tiam1 protein abundance.…”

Section: Tiam1 As a Transactivation Target And Downstream Effector Ofmentioning

confidence: 96%

CtBP2 Promotes Human Cancer Cell Migration by Transcriptional Activation of Tiam1

Paliwal

Parker

et al. 2012

Genes & Cancer

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The mammalian COOH-terminal binding proteins (CtBPs) CtBP1 and CtBP2 are metabolically regulated transcriptional co-repressors that are degraded upon acute exposure to the alternative reading frame (ARF) tumor suppressor. We reported previously that CtBP stimulates cell migration in certain contexts via repression of PTEN transcription and activation of the phosphatidylinositol 3-kinase (PI3K) pathway. We have now identified an additional and direct mechanism for CtBP stimulation of cell migration via regulation of T-cell lymphoma invasion and metastasis 1 (Tiam1) protein. Tiam1 is a guanine nucleotide exchange factor (GEF) for Rac GTPase that plays a critical role in regulating cell adhesion, invasion, and migration and has been directly implicated in the promotion of cancer progression and metastasis. We noted a strict positive correlation between CtBP2 and Tiam1 expression levels and that CtBP promotion of cell migration required CtBP-dependent transcriptional activation of Tiam1. RNA interference (RNAi)-mediated knockdown of CtBP2 in human colon or lung carcinoma cells led to decreased Tiam1 protein and mRNA expression, while overexpression of CtBP2 increased Tiam1 expression levels. RNAi and overexpression studies also demonstrated that Tiam1 is a key downstream mediator of CtBP2-mediated cell migration. An analysis of the Tiam1 promoter revealed binding sites for the CtBP-interacting Kruppel-like factor 8 (KLF8), and a Tiam1 promoter luciferase reporter was induced in the presence of both KLF8 and CtBP2, consistent with KLF8-dependent CtBP transactivation of Tiam1. Chromatin immunoprecipitation analyses demonstrated CtBP2 occupancy of the Tiam1 promoter that was dependent on the presence of KLF8. Our results indicate that Tiam1 is a transcriptional activation target of CtBP2 and that this interaction promotes the pro-oncogenic function of CtBP2 leading to cancer cell migration. Transcriptional activation thus plays a role in CtBP pro-oncogenic functions along with the previously characterized CtBP co-repressor function.

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

Cited by 53 publications

References 26 publications

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes

CtBP2 Promotes Human Cancer Cell Migration by Transcriptional Activation of Tiam1

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