Developmental regulation of yolk sac hematopoiesis by Krüppel-like factor 6

Matsumoto, Nobuyuki; Kubo, Atsushi; Liu, Huixian; Akita, Kuniharu; Laub, Friedrich; Ramirez, Francesco; Keller, Gordon; Friedman, Scott L.

doi:10.1182/blood-2005-05-1916

Cited by 125 publications

(134 citation statements)

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“…Moreover, KLF6 is expressed from very early stages during human placental development, colocalizing with PSG transcripts and proteins within the same tissue structures and cell types, suggesting a relevant role of this factor for the transcriptional regulation of PSG genes in vivo (14). Additionally, the klf62/2 mice phenotype is characterized by developmental defects including impaired placental development and poorly defined liver contributing to early lethality along with failures in the yolk sac vascularization (15). Besides the enriched KLF6 expression in placenta, its transcript is also detected in all mammalian tissues, although at lower levels; whereas, marginal expression was detected at the embryo proper during mice embryogenesis (12).…”

Section: Discovery Of Klf6: a Key Regulator Of Cell Homeostasis And Dmentioning

confidence: 99%

“…Nevertheless, a number of other studies established that genetic alterations of KLF6 were infrequently observed in distinct types of human cancers or even the klf6 gene expression was enhanced in some tumors (29). Moreover, target disruption of the klf6 gene severely impaired ES cell proliferation (15). In addition, p21…”

Section: Discovery Of Klf6: a Key Regulator Of Cell Homeostasis And Dmentioning

confidence: 99%

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Biology of Krüppel‐like factor 6 transcriptional regulator in cell life and death

2010

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SummaryAn essential role for the Krü ppel-like transcription factor family has been determined in the regulation of remarkable processes including cell proliferation, differentiation, signal transduction, oncogenesis, and cell death. A member of this group, Krü ppel-like factor 6 (KLF6), identified on the basis of its ability to regulate a group of genes belonging to the carcinoembryonic antigen gene family, has been involved in human carcinogenesis. Early studies proposed a tumor suppressor function for KLF6 because of its ability to reduce cell proliferation through several biochemical mechanisms including regulation of cell cycle components, oncogene products, and apoptosis. Mutations within the klf6 gene, decreased expression and/or loss-of-heterozygosity were associated with the development of different human malignancies, and, hence, further supporting the tumor suppressor function of KLF6. This view has been challenged by other studies in distinct types of human cancers describing infrequent genetic alterations of klf6 gene or even enhanced expression in some tumors. The scenario about KLF6 function became still more complex as the description of oncogenic KLF6 splice variant 1 (SV1) with dominant negative activity against the wild type KLF6 (wtKLF6) protein. Additionally, increased evidence is suggesting that KLF6 is a bonafide target of several signaling cascades, which ultimate regulatory effect on this protein could drive decisions of cell life and death, facing the dilemma about how wtKLF6 could be involved in both processes. These apparently conflicting situations, emerged by apparently opposite effects mediated by wtKLF6, may be related, at least in part, to the biological cross-talk with the c-Jun oncoprotein. Depending on the stimulus received by the cell, wtKLF6 interaction with c-Jun determines different cell outcomes such as proliferation control or apoptosis. Thus, KLF6 responsiveness represents a kind of cell warning signal on receiving different stimuli, including oncogenic activation and microbial infections, orchestrating the implementation of proliferation and apoptotic programs.

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Section: Discovery Of Klf6: a Key Regulator Of Cell Homeostasis And Dmentioning

confidence: 99%

Section: Discovery Of Klf6: a Key Regulator Of Cell Homeostasis And Dmentioning

confidence: 99%

Biology of Krüppel‐like factor 6 transcriptional regulator in cell life and death

2010

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“…In light of the mounting number of studies reporting KLF6 involvement in HCC through LOH and/or mutation, and to further establish a direct relationship between KLF6 and p21 in vivo, we characterized the livers of KLF6 heterozygous (Het) mice that had been generated by homologous recombination and targeting of KLF6 exon 2, as described previously (Matsumoto et al, 2006). Two independent lines of mice, AH2 and CH2, were generated and Het AH2 mice were examined.…”

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confidence: 99%

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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“…All Klf knockouts generated thus far are embryonic lethal (20 -22), including the Klf6 knock-out mice (23). Because prostate development begins in late gestation and continues postnatally, we overcame embryonic lethality to study the role of Klf6 in prostate development and tumorigenesis by generating a prostate-specific deletion of the Klf6 gene using a Cre-lox recombination approach.…”

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confidence: 99%

Prostate-specific Klf6 Inactivation Impairs Anterior Prostate Branching Morphogenesis through Increased Activation of the Shh Pathway

Leow¹,

Wang²,

Ross

et al. 2009

Journal of Biological Chemistry

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Krüppel-like factor 6 (Klf6) belongs to a family of zinc finger transcription factors known to play a role in development and tumor suppression. Although Klf6 is highly mutated in prostate cancer, its function in prostate development is unknown. We have generated a prostate-specific Klf6-deficient mouse model and report here a novel role for Klf6 in the regulation of prostate branching morphogenesis. Importantly, our study reveals a novel relationship between Klf6 and the Shh pathway. Klf6-deficiency leads to elevated levels of hedgehog pathway components (Shh, Ptc, and Gli) and loss of their localized expression, which in turn causes impaired lateral branching.

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Developmental regulation of yolk sac hematopoiesis by Krüppel-like factor 6

Cited by 125 publications

References 67 publications

Biology of Krüppel‐like factor 6 transcriptional regulator in cell life and death

Biology of Krüppel‐like factor 6 transcriptional regulator in cell life and death

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

Prostate-specific Klf6 Inactivation Impairs Anterior Prostate Branching Morphogenesis through Increased Activation of the Shh Pathway

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