Foster, K. W. et al. Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia. Oncogene 24, 1491-1500

Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Oncogene (Impact Factor: 8.46). 03/2005; 24(9):1491-500. DOI: 10.1038/sj.onc.1208307
Source: PubMed


KLF4/GKLF normally functions in differentiating epithelial cells, but also acts as a transforming oncogene in vitro. To examine the role of this zinc finger protein in skin, we expressed the wild-type human allele from inducible and constitutive promoters. When induced in basal keratinocytes, KLF4 rapidly abolished the distinctive properties of basal and parabasal epithelial cells. KLF4 caused a transitory apoptotic response and the skin progressed through phases of hyperplasia and dysplasia. By 6 weeks, lesions exhibited nuclear KLF4 and other morphologic and molecular similarities to squamous cell carcinoma in situ. p53 determined the patch size sufficient to establish lesions, as induction in a mosaic pattern produced skin lesions only when p53 was deficient. Compared with p53 wild-type animals, p53 hemizygous animals had early onset of lesions and a pronounced fibrovascular response that included outgrowth of subcutaneous sarcoma. A KLF4-estrogen receptor fusion protein showed tamoxifen-dependent nuclear localization and conditional transformation in vitro. The results suggest that KLF4 can function in the nucleus to induce squamous epithelial dysplasia, and indicate roles for p53 and epithelial-mesenchymal signaling in these early neoplastic lesions.

Download full-text


Available from: Iúri Drumond Louro
  • Source
    • "Moreover, RFs that enhance iPSC formation may undermine subsequent clinical applications, as illustrated by CMYC, which collaborates with other RFs to enhance iPSC formation but induces tumors in iPSC-derived tissues9. Similarly, ectopic OCT4 and KLF4 promote epithelial dysplasias1011. For these reasons, various strategies have been developed to produce transgene-free iPSCs, including: loxP flanked vectors12, excisable transposons13, adenovirus1415 and Sendai virus16 vectors and non-integrating episomal vectors1718. Other approaches have moved completely away from DNA-based expression vectors, including: synthetic modified RNA19, epigenetic regulation by chemical compounds (see20 for a review) and direct uptake of cell-penetrating RF proteins2122. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The production of pluripotent stem cells (iPSCs) for therapeutic applications will require practical methods to achieve tight temporal and quantitative control of reprogramming factor (RF) expression, while avoiding the mutagenic potential of gene transfer. Toward this end, we have developed cell-permeable RF proteins (CP-RFs) incorporating newly developed macromolecule transduction domains (MTDs). Treatment of human dermal fibroblasts (HDFs) with combinations of cell-permeable OCT4, SOX2, KLF4, CMYC and either NANOG or LIN28 proteins induced the outgrowth of stem cell-like colonies (iSCs). iSC colonies generated with CP-RFs resembled embryonic stem cells with regard to morphology, biomarker expression, and extended capacity for self-renewal, but failed to expand as iPSC or ES cell lines. Partial reprogramming appears to be a common response to protein-based delivery of programming factors into somatic cells.
    Full-text · Article · Mar 2014 · Scientific Reports
  • Source
    • "Yet, Klf4 has also been found highly expressed in dysplastic epithelium, in breast cancers and in squamous cell carcinoma of the oropharynx [18]. Moreover, Klf4 has been shown to act as an oncogene cooperating with c-Myc in the transformation of cells, and the inducible expression of Klf4 in mice is sufficient to provoke skin dysplasia and squamous cell carcinoma [19], [20]. In contrast, database-mining analysis reveals a correlation between low Klf4 expression and an increased incidence of malignant breast carcinoma [21]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We have identified the zinc-finger transcription factor Kruppel-like factor 4 (Klf4) among the transcription factors that are significantly downregulated in their expression during epithelial-mesenchymal transition (EMT) in mammary epithelial cells and in breast cancer cells. Loss and gain of function experiments demonstrate that the down-regulation of Klf4 expression is required for the induction of EMT and for metastasis . In addition, reduced Klf4 expression correlates with shorter disease-free survival of subsets of breast cancer patients. Yet, reduced expression of Klf4 also induces apoptosis in cells undergoing TGFβ-induced EMT. Chromatin immunoprecipitation/deep-sequencing in combination with gene expression profiling reveals direct Klf4 target genes, including E-cadherin (), N-cadherin (), vimentin (), β-catenin (), VEGF-A (), endothelin-1 () and Jnk1 (). Thereby, Klf4 acts as a transcriptional activator of epithelial genes and as a repressor of mesenchymal genes. Specifically, increased expression of Jnk1 () upon down-regulation of its transcriptional repressor Klf4 is required for EMT cell migration and for the induction of apoptosis. The data demonstrate a central role of Klf4 in the maintenance of epithelial cell differentiation and the prevention of EMT and metastasis.
    Full-text · Article · Oct 2013 · PLoS ONE
  • Source
    • "Krüppel-like factor 4 (KLF4) [1,2] belongs to the Krüppel-like factor family of zinc-finger transcription factors that are involved in numerous important cellular processes such as growth, development, differentiation, proliferation, inflammation, apoptosis, and somatic cell reprogramming. KLF4 has been shown in a context-dependent manner to be an oncogene or tumor suppressor [3], as respectively demonstrated by the high levels of KLF4 in primary breast ductal carcinoma and oral squamous cell carcinoma [4,5] and decreased levels of KLF4 in a variety of other human cancers including esophageal, gastric, bladder, pancreatic, colorectal, lung and urinary bladder cancers [6-14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Kruppel-like factor 4 (KLF4) is a member of the KLF family of transcription factors and regulates proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers including colorectal cancer. We previously showed that KLF4 inhibits cell cycle progression following DNA damage and that mouse embryonic fibroblasts (MEFs) null for Klf4 are genetically unstable, as evidenced by increased rates of cell proliferation, and the presence of DNA double strand breaks (DSBs), centrosome amplification, chromosome aberrations and aneuploidy. To determine whether re-expression of Klf4 corrects the observed genetic instability in MEFs null for Klf4 (Klf4-/-), we transfected Klf4-/-MEFs with Klf4-expressing plasmids and compared the results to wild type (Klf4+/+) and untransfected or mock-transfected Klf4-/-MEFs. We show that overexpression of Klf4 in Klf4-/-MEFs reduced cell proliferation rates and the proportion of cells with DSBs, abnormal centrosome numbers, aneuploidy and micronuclei. In addition, Klf4-transfected Klf4-/-MEFs exhibited a more robust DNA damage repair response as demonstrated by the greater rate in disappearance of gamma-H2AX and 53BP1 foci following gamma-irradiation. Taken together these findings provide evidence that KLF4 plays a crucial role in the maintenance of genetic stability by modulating the DNA damage response and repair processes.
    Full-text · Article · Aug 2013 · Molecular Cancer
Show more