Krüppel-like Factors: Three Fingers in Many Pies

Bieker, James J.

doi:10.1074/jbc.r100043200

Cited by 559 publications

(509 citation statements)

References 71 publications

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“…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.…”

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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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“…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.…”

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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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“…Combined, these data suggest that haploinsufficiency of the KLF6 gene may regulate cellular proliferation in vivo through decreased transcriptional activation of the cyclin-dependent kinase inhibitor p21. Oncogene (2007) 26, 4428-4434; doi:10.1038/sj.onc.1210223; published online 5 February 2007 Keywords: KLF6; Kruppel-like factor; tumor-suppressor gene; p21; haploinsufficiency Kruppel-like factor 6 (KLF6) belongs to the Kruppellike family of transcription factors, which play roles in the regulation of diverse cellular processes including development, differentiation, proliferation and apoptosis (Bieker, 2001). Functional inactivation of the KLF6 gene occurs through several mechanisms, including loss of heterozygosity (LOH), somatic mutation and/or increased alternative splicing that yields a dominantnegative splice isoform, KLF6-SV1.…”

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In vivo regulation of p21 by the Kruppel-like factor 6 tumor-suppressor gene in mouse liver and human hepatocellular carcinoma

et al. 2007

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Kruppel-like factor (KLF) 6 is a tumor-suppressor gene functionally inactivated by loss of heterozygosity, somatic mutation and/or alternative splicing that generates a dominant-negative splice form, KLF6-SV1. Wild-type KLF6 (wtKLF6) expression is decreased in many human malignancies, which correlates with reduced patient survival. Additionally, loss of the KLF6 locus in the absence of somatic mutation in the remaining allele occurs in a number of human cancers, raising the possibility that haploinsufficiency of the KLF6 gene alone contributes to cellular growth dysregulation and tumorigenesis. Our earlier studies identified the cyclin-dependent kinase inhibitor p21 as a transcriptional target of the KLF6 gene in cultured cells, but not in vivo. To address this issue, we have generated two genetic mouse models to define the in vivo role of KLF6 in regulating cell proliferation and p21 expression. Transgenic overexpression of KLF6 in the liver resulted in a runted phenotype with decreased body and liver size, with evidence of decreased hepatocyte proliferation, increased p21 and reduced proliferating cell nuclear antigen expression. In contrast, mice with targeted deletion of one KLF6 allele (KLF6 þ /À) display increased liver mass with reduced p21 expression, compared to wild type littermates. Moreover, in primary hepatocellular carcinoma samples, there is a significant correlation between wtKLF6 and p21 mRNA expression. Combined, these data suggest that haploinsufficiency of the KLF6 gene may regulate cellular proliferation in vivo through decreased transcriptional activation of the cyclin-dependent kinase inhibitor p21. Oncogene (2007) 26, 4428-4434; doi:10.1038/sj.onc.1210223; published online 5 February 2007 Keywords: KLF6; Kruppel-like factor; tumor-suppressor gene; p21; haploinsufficiency Kruppel-like factor 6 (KLF6) belongs to the Kruppellike family of transcription factors, which play roles in the regulation of diverse cellular processes including development, differentiation, proliferation and apoptosis (Bieker, 2001). Functional inactivation of the KLF6 gene occurs through several mechanisms, including loss of heterozygosity (LOH), somatic mutation and/or increased alternative splicing that yields a dominantnegative splice isoform, KLF6-SV1. KLF6 dysregulation has been demonstrated in a number of human cancers including prostate (Narla et al., 2001;Chen et al., 2003), colorectal , non-smallcell lung (Ito et al., 2004), gastric (Cho et al., 2005), nasopharyngeal (Chen et al., 2002), hepatocellular (Kremer-Tal et al., 2004) and ovarian carcinomas (DiFeo et al., 2006b) as well as glioma (Jeng et al., 2003). Furthermore, decreased KLF6 mRNA expression is associated with reduced patient survival in prostate (Singh et al., 2002;Glinsky et al., 2004) and lung cancers (Kettunen et al., 2004). Interestingly, reconstitution of KLF6 decreases cell proliferation and reverts tumorigenicity in glioblastoma cell lines (Kimmelman et al., 2004).Depending on the cell type and context, KLF6's growth-suppressive prop...

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“…Krüppel-like factors serve as core transcription factors and participate in regulation of numerous mammalian genes (Bieker, 2001;Black et al, 2001). One of the factors, KLF6, is thought to play a role in repair of vascular injury and in tissue remodelling (Kojima et al, 2000).…”

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Analysis of human prostate cancers and cell lines for mutations in the TP53 and KLF6 tumour suppressor genes

et al. 2003

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A recent report suggests that the KLF6 gene encoding the Krüppel-like factor 6 protein is a frequently mutated, putative tumour suppressor gene in prostate cancer. The aims of the present study were to confirm these initial findings by determining the frequency of exon2 KLF6 mutations in a cohort of European prostate cancer patients, and to investigate whether there was evidence for mutational inactivation of both the KLF6 and TP53 tumour suppressor loci in some tumours. We examined 32 primary prostate tumours and three prostate tumour cell lines for mutations by PCR amplification and direct dideoxy sequencing (KLF6), and by oligonucleotide microarray (p53GeneChipt) analysis and dideoxy sequencing (TP53). Whereas TP53 mutations typical of prostate cancer were found at a frequency consistent with the literature, no KLF6 mutations were found in any of the tumour samples nor in the three prostate cancer cell lines.

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Krüppel-like Factors: Three Fingers in Many Pies

Cited by 559 publications

References 71 publications

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

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

In vivo regulation of p21 by the Kruppel-like factor 6 tumor-suppressor gene in mouse liver and human hepatocellular carcinoma

Analysis of human prostate cancers and cell lines for mutations in the TP53 and KLF6 tumour suppressor genes

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