Identification of Candidate Klf4 Target Genes Reveals the Molecular Basis of the Diverse Regulatory Roles of Klf4 in the Mouse Cornea

Swamynathan, Sudha; Davis, Judith A.; Piatigorsky, Joram

doi:10.1167/iovs.08-1811

Cited by 60 publications

(100 citation statements)

References 69 publications

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“…KLF4 is expressed in differentiated, nonproliferating cells, where it serves to suppress proliferation. Gene expression profiling experiments show that KLF4 suppresses expression of proliferation-associated genes and activates expression of differentiation-associated genes (2)(3)(4)(5). KLF4 has an important regulatory role in epithelia.…”

Section: Klf4mentioning

confidence: 99%

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Protein Kinase C δ Increases Kruppel-like Factor 4 Protein, which Drives Involucrin Gene Transcription in Differentiating Keratinocytes

Chew

Adhikary²,

Xu³

et al. 2013

Journal of Biological Chemistry

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Background: KLF4 is an important regulator of terminal differentiation and barrier formation in epidermis, but its mechanism of action is not well understood. Results: PKC␦ increases KLF4, which increases hINV expression by interaction at specific elements in the hINV promoter. Conclusion: KLF4 drives expression of involucrin in response to differentiation stimuli. Significance: This study provides detailed information regarding the mechanism of KLF4 regulation of keratinocyte differentiation.

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Section: Klf4mentioning

confidence: 99%

“…KLF4 activates expression of cyclin-dependent kinase inhibitors (2,13,14) and cooperates with p53 to increase p21…”

Section: Klf4mentioning

confidence: 99%

Protein Kinase C δ Increases Kruppel-like Factor 4 Protein, which Drives Involucrin Gene Transcription in Differentiating Keratinocytes

Chew

Adhikary²,

Xu³

et al. 2013

Journal of Biological Chemistry

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“…KLF4, therefore, joins an increasingly long list of regulators that are kept at bay in the lower skin layers by p63's direct negative control. Transcriptional profiling has been performed by overexpressing KLF4 in the colon cancer cell line RKO and in an elegant system of corneal cells derived from KLF4-conditional null mice (Swamynathan et al, 2008): this latter study, in particular, reported notorious targets of p63, such as c-Jun and PDGFb-RII, among genes upregulated by KLF4, and FGF-R2, Id2 and C/EBPd, among the repressed ones. The latter is particularly interesting, as it was placed upstream of p63 in the regulation of stem cells of the corneal limbus (Barbaro et al, 2007), and targets of C/EBPd, such as Desmocollin 3 and other genes coding for desmosomal proteins (Smith et al, 2004), are also targets of KLF4.…”

Section: P63 and Klf4 In Normal Skinmentioning

confidence: 99%

“…Profiling experiments have shown that KLF4 activates genes that inhibit proliferation, and represses genes that promote it Whitney et al, 2006;Swamynathan et al, 2008). However, studies on KLF4 in tumors suggest that its role is extremely complex and variegated.…”

mentioning

confidence: 99%

“…Interestingly, maintaining elevated levels of KLF4 prevents apoptosis mediated by p53 (Ghaleb et al, 2007), and elimination of KLF4 induction leads to apoptosis in cells treated with nonapoptotic doses of DNA-damaging agents (Zhou et al, 2009). KLF4 activates CDKIs, p21, p27 and p57 (Chen et al, 2001Wei et al, 2006;Swamynathan et al, 2008); in particular, it cooperates with p53 in activating p21 (Zhang et al, 2000). KLF4 represses p53 transcription by binding to GC boxes in the p53 promoter: under these conditions, the levels of p21 and Cyclin D1 are crucial for deciding as to whether KLF4 exerts a tumor suppressive-high p21 or oncogenic-high Cyclin D1 activity (Rowland et al, 2005).…”

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confidence: 99%

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Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

et al. 2010

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Genetic experiments established that p63 is crucial for the development and maintenance of pluri-stratified epithelia and KLF4 for the barrier function of the skin. KLF4 is one of the factors that reprogram differentiated cells to iPS. We investigated the relationship between p63 and KLF4 using RNA interference, overexpression, chromatin immunoprecipitation and transient transfections with reporter constructs. We find that p63 directly represses KLF4 in normal keratinocytes (KCs) by binding to upstream promoter sites. Unlike p63, KLF4 levels are high in the upper layers of human skin and increase upon differentiation of KCs in vitro. In HaCaT KCs, which harbor two mutant alleles of p53, inactivation of p63 and of mutant p53 leads to KLF4 repression. p63 and p53 mutants are bound to sites in the KLF4 core promoter. Importantly, expression of the H179Y and R282Q p53 mutants in primary KCs is sufficient to activate endogenous KLF4. Finally, immunohistochemical analysis of tissue arrays confirms increased coexpression of KLF4 and mutant p53 in squamous cell carcinomas. Our data indicate that suppression of KLF4 is part of the growth-promoting strategy of p63 in the lower layers of normal epidermis, and that tumor-predisposing p53 mutations hijack p63 to a different location on the promoter, turning it into an activator of this reprogramming factor.

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Targeted deletion of Dicer disrupts lens morphogenesis, corneal epithelium stratification, and whole eye development

Piatigorsky

2009

Developmental Dynamics

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Dicer, a ribonuclease essential for miRNA processing, is expressed abundantly in developing mouse cornea and lens. We studied the roles of Dicer and miRNAs in eye development by conditionally deleting the Dicer gene in the mouse lens and corneal epithelium. Adult Dicer conditional null (DicerCN) mice had severe microphthalmia with no discernible lens and a poorly stratified corneal epithelium. Targeted deletion of Dicer effectively inhibited miRNA processing in the developing lens at 12.5 day of embryogenesis (E12.5). Lens development initiated normally but underwent progressive dystrophy between E14.5 and E18.5. Microarray analysis revealed activation of P53 signaling in DicerCN lenses at E13.5, consistent with increased apoptosis and reduced cell proliferation between E12.5 and E14.5. Expression of Pax6 and other lens developmental transcription factors were not greatly affected between E12.5 and E14.5 but decreased as the lens degenerated. Our data indicated an indispensible role for Dicer and miRNAs in lens and corneal development.

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Identification of Candidate Klf4 Target Genes Reveals the Molecular Basis of the Diverse Regulatory Roles of Klf4 in the Mouse Cornea

Abstract: Functionally diverse candidate Klf4 target genes were identified, revealing the molecular basis of the diverse aspects of the Klf4CN corneal phenotype. These results establish Klf4 as an important node in the genetic network of transcription factors regulating the corneal homeostasis.

Cited by 60 publications

References 69 publications

Protein Kinase C δ Increases Kruppel-like Factor 4 Protein, which Drives Involucrin Gene Transcription in Differentiating Keratinocytes

Protein Kinase C δ Increases Kruppel-like Factor 4 Protein, which Drives Involucrin Gene Transcription in Differentiating Keratinocytes

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

Targeted deletion of Dicer disrupts lens morphogenesis, corneal epithelium stratification, and whole eye development

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