Ligand-dependent Corepressor (LCoR) Recruitment by Krüppel-like Factor 6 (KLF6) Regulates Expression of the Cyclin-dependent Kinase Inhibitor CDKN1A Gene

Calderon, Mario R.; Verway, Mark; An, Beum Soo; DiFeo, Analisa; Bismar, Tarek A.; Ann, David K.; Martignetti, John A.; Shalom‐Barak, Tali; White, John H.

doi:10.1074/jbc.m111.311605

Cited by 37 publications

(54 citation statements)

References 48 publications

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“…Consistently, knockdown of klf6a decreased hepatocyte proliferation by upregulating cdkn1a in zebrafish (Zhao et al, 2010). Furthermore, it has been demonstrated that klf6 represses cdkn1a by a transcriptional co-repressor complex (Calderon et al, 2012). Because klf6 is known to be a transcriptional activator or repressor, it might play distinct roles depending on the developmental and tissue-specific contexts.…”

Section: Discussionmentioning

confidence: 78%

Genome-wide analysis of the zebrafish Klf family identifies two genes important for erythroid maturation

Xue

Gao

Liu

2015

Developmental Biology

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Krüppel-like transcription factors (Klfs), each of which contains a CACCC-box binding domain, have been investigated in a variety of developmental processes, such as angiogenesis, neurogenesis and somatic-cell reprogramming. However, the function and molecular mechanism by which the Klf family acts during developmental hematopoiesis remain elusive. Here, we report identification of 24 Klf family genes in zebrafish using bioinformatics. Gene expression profiling shows that 6 of these genes are expressed in blood and/or vascular endothelial cells during embryogenesis. Loss of function of 2 factors (klf3 or klf6a) leads to a decreased number of mature erythrocytes. Molecular studies indicate that both Klf3 and Klf6a are essential for erythroid cell differentiation and maturation but that these two proteins function in distinct manners. We find that Klf3 inhibits the expression of ferric-chelate reductase 1b (frrs1b), thereby promoting the maturation of erythroid cells, whereas Klf6a controls the erythroid cell cycle by negatively regulating cdkn1a expression to determine the rate of red blood cell proliferation. Taken together, our study provides a global view of the Klf family members that contribute to hematopoiesis in zebrafish and sheds new light on the function and molecular mechanism by which Klf3 and Klf6a act during erythropoiesis in vertebrates.

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Section: Discussionmentioning

confidence: 78%

Genome-wide analysis of the zebrafish Klf family identifies two genes important for erythroid maturation

Xue

Gao

Liu

2015

Developmental Biology

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“…Immunoprecipitations were performed as previously described (8). Samples were immunoprecipitated with α-IgG, α-HA (ab1424 or custom) or α-FLAG (F1804).…”

Section: Methodsmentioning

confidence: 99%

“…Knockdowns were performed essentially as previously described (8). Briefly, MCF-7/MCF10A/T47D cells were plated in 6-wells plates.…”

Section: Methodsmentioning

confidence: 99%

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Ligand-dependent corepressor contributes to transcriptional repression by C2H2 zinc-finger transcription factor ZBRK1 through association with KRAB-associated protein-1

Calderon

Verway

Benslama

et al. 2014

Nucleic Acids Research

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We identified a novel interaction between ligand-dependent corepressor (LCoR) and the corepressor KRAB-associated protein-1 (KAP-1). The two form a complex with C2H2 zinc-finger transcription factor ZBRK1 on an intronic binding site in the growth arrest and DNA-damage-inducible α (GADD45A) gene and a novel site in the fibroblast growth factor 2 (FGF2) gene. Chromatin at both sites is enriched for histone methyltransferase SETDB1 and histone 3 lysine 9 trimethylation, a repressive epigenetic mark. Depletion of ZBRK1, KAP-1 or LCoR led to elevated GADD45A and FGF2 expression in malignant and non-malignant breast epithelial cells, and caused apoptotic death. Loss of viability could be rescued by simultaneous knockdowns of FGF2 and transcriptional coregulators or by blocking FGF2 function. FGF2 was not concurrently expressed with any of the transcriptional coregulators in breast malignancies, suggesting an inverse correlation between their expression patterns. We propose that ZBRK1, KAP-1 and LCoR form a transcriptional complex that silences gene expression, in particular FGF2, which maintains breast cell viability. Given the broad expression patterns of both LCoR and KAP-1 during development and in the adult, this complex may have several regulatory functions that extend beyond cell survival, mediated by interactions with ZBRK1 or other C2H2 zinc-finger proteins.

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“…Altered expression profiles of KLF6 and its splice variants KLF6-SV1 have been observed in multiple cancer types. 1 Remarkable overexpression of KLF6-SV1, a dominant-negative spliced isoform with antagonistic function against KLF6-FL, has been identified in liver cancer, 16,21 lung cancer, 22 prostate cancer, 20,23,[42][43][44] breast cancer 24,[45][46][47] with reduced survival and unfavorable outcome. Conversely, siRNAmediated inhibition of KLF6-SV1 attenuated the cancer cell proliferation both in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

Identification of miRNAs that specifically target tumor suppressive KLF6-FL rather than oncogenic KLF6-SV1 isoform

et al. 2014

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Ligand-dependent Corepressor (LCoR) Recruitment by Krüppel-like Factor 6 (KLF6) Regulates Expression of the Cyclin-dependent Kinase Inhibitor CDKN1A Gene

Cited by 37 publications

References 48 publications

Genome-wide analysis of the zebrafish Klf family identifies two genes important for erythroid maturation

Genome-wide analysis of the zebrafish Klf family identifies two genes important for erythroid maturation

Ligand-dependent corepressor contributes to transcriptional repression by C2H2 zinc-finger transcription factor ZBRK1 through association with KRAB-associated protein-1

Identification of miRNAs that specifically target tumor suppressive KLF6-FL rather than oncogenic KLF6-SV1 isoform

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