A new role for the Krüppel-like transcription factor KLF6 as an inhibitor of c-Jun proto-oncoprotein function

Slavin, Daniela A; Koritschoner, Nicolás P.; Prieto, Claudio; López-Díaz, Fernando J.; Chatton, Bruno; Bocco, José Luis

doi:10.1038/sj.onc.1208020

Cited by 83 publications

(80 citation statements)

References 39 publications

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“…29 Several KLFs were reported to be phosphorylated and their transcriptional activities were changed by the modifications. [30][31][32] We found that when several serines on the KLF9 protein were mutated to alanines, its transcriptional activities detected by luciferase report assay for the PPARg2 promoter were greatly enhanced (unpublished data). However, whether post-translational modifications really happened to endogenous KLF9 in adipogenesis needs to be further investigated.…”

Section: Discussionmentioning

confidence: 92%

Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis

et al. 2010

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Krü ppel-like factors (KLFs) as a family of zinc-finger transcription factors involve in the regulation of many physiological processes. In these studies, KLF9 was characterized for its role in adipogenesis. The expression of KLF9 was markedly upregulated during the middle stage of 3T3-L1 adipocyte differentiation, and inhibition of KLF9 by RNAi impaired adipogenesis. Using promoter deletion and mutation analysis, we identified two KLF9-binding sites within the 0.6-kb region of the PPARc2 proximal promoter, indicating that KLF9 interacts with the PPARc2 promoter. Furthermore, we found that KLF9 could synergistically activate PPARc2 promoter by directly interacting with C/EBPa. In addition, overexpression of PPARc2 rescued the impairment of adipocyte differentiation induced by KLF9 knockdown, which supports that PPARc2 is a downstream target of KLF9. Collectively, our results indicate KLF9 as a key pro-adipogenic transcription factor through regulation of PPARc2 expression with C/EBPa at the middle stage of adipogenesis.

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Section: Discussionmentioning

confidence: 92%

Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis

et al. 2010

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“…As low KLF6 and E2F1 protein levels in crude lysates of REH cells could not be detected after stripping of the membrane, we show two different KLF6 IPs, one probed with anti-KLF6 and the other with anti-E2F1 antibody. C-jun has been shown to interact with KLF6 (Slavin et al, 2004) and served as a positive control for the IP. As shown in Figure 5c, immunoblotting with E2F1 antibody identified E2F1 in the anti-KLF6 immunoprecipitates demonstrating that KLF6 and E2F1 can be in the same protein complex.…”

Section: E2f1 and Klf6 Cooperate In Activating Dapk2mentioning

confidence: 99%

DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function

et al. 2008

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Death-associated protein kinase 2 (DAPK2) belongs to a family of proapoptotic Ca 2 þ /calmodulin-regulated serine/ threonine kinases. We recently identified DAPK2 as an enhancing factor during granulocytic differentiation. To identify transcriptional DAPK2 regulators, we cloned 2.7 kb of the 5 0 -flanking region of the DAPK2 gene. We found that E2F1 and Kru¨ppel-like factor 6 (KLF6) strongly activate the DAPK2 promoter. We mapped the E2F1 and KLF6 responsive elements to a GC-rich region 5 0 of exon 1 containing several binding sites for KLF6 and Sp1 but not for E2F. Moreover, we showed that transcriptional activation of DAPK2 by E2F1 and KLF6 is dependent on Sp1 using Sp1/KLF6-deficient insect cells, mithramycin A treatment to block Sp1-binding or Sp1 knockdown cells. Chromatin immunoprecipitation revealed recruitment of Sp1 and to lesser extent that of E2F1 and KLF6 to the DAPK2 promoter. Activation of E2F1 in osteosarcoma cells led to an increase of endogenous DAPK2 paralleled by cell death. Inhibition of DAPK2 expression resulted in significantly reduced cell death upon E2F1 activation. Similarly, KLF6 expression in H1299 cells increased DAPK2 levels accompanied by cell death that is markedly decreased upon DAPK2 knockdown. Moreover, E2F1 and KLF6 show cooperation in activating the DAPK2 promoter. In summary, our findings establish DAPK2 as a novel Sp1-dependent target gene for E2F1 and KLF6 in cell death response.

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“…6 This has been proven in several in vitro 5 and in vivo assays. 7 KLF6 is believed to regulate cancer development and progression through the downregulation of the c-Jun oncoprotein 8 and the activation of E-cadherin. 9 The reported frequency of KLF6 mutations in different types of human cancer varies in the different published studies.…”

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confidence: 99%

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

et al. 2008

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Krü ppel-like factor 6 (KLF6) has been reported to act as a tumor suppressor gene involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. Many studies suggest that KLF6 is inactivated by allelic loss and somatic mutation. However, there is a high variability in the reported frequency of mutations (from 1 to 55%). TP53 also regulates the cell cycle through the activation of p21. In prostate cancer, the reported frequency of TP53 mutations ranges from 3 to 42%. In all these reports, there is a considerable degree of methodological heterogeneity. Our aim was to determine the frequency of KLF6 and TP53 mutations in a welldefined group of prostate tumors with different stages and Gleason grades. The four exons of KLF6 and exons 4-9 of TP53 were studied in 103 cases, including 90 formalin-fixed, paraffin-embedded (FFPE) and 13 frozen samples. All tumors were analyzed through PCR and direct sequencing. All changes found were confirmed by a second independent PCR and sequencing reaction. For KLF6, mutation (E227G) was only detected in one tumor (1%) and for TP53, three different mutations (L130H, H214R, and Y234C) were detected in five tumors (5%). This low mutation index is in keeping with recent papers on the subject. Our study strongly supports the notion that KLF6 and TP53 mutations are not frequent events in prostate cancer. When using FFPE tissues, it is mandatory to perform at least two independent rounds of PCR and sequencing to confirm mutations and exclude Taq polymerase-induced artifacts. Two of these genes are Krü ppel-like factor 6 (KLF6) and TP53.KLF6 is a transcription factor that interacts with DNA through three zinc-fingers in its COOHterminal domain. KLF6 belongs to the KLF family, a family that is broadly involved in cell differentiation, development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. 5 It has been suggested that KLF6 could be involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. 6 This has been proven in several in vitro 5 and in vivo assays. 7 KLF6 is believed to regulate cancer development and progression through the downregulation of the c-Jun oncoprotein 8 and the activation of E-cadherin. 9 The reported frequency of KLF6 mutations in different types of human cancer varies in the different published studies. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In prostate cancer, four studies have analyzed the frequency of KLF6 mutations. 6,[30][31][32] In the first published study, Narla et al 6 showed a very high frequency, 55%, whereas in the following study, Chen et al 30 obtained a lower frequency, around 15%. The results of two recent reports provided frequencies of 0 and 1%. 31,32 It should be noted that there were considerable

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A new role for the Krüppel-like transcription factor KLF6 as an inhibitor of c-Jun proto-oncoprotein function

Cited by 83 publications

References 39 publications

Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis

Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis

DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

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