Krüppel-like factor 4 (KLF4) is a transcription factor highly conserved in evolution. It is particularly well known for its role in inducing pluripotent stem cells. In addition, KLF4 plays many roles in cancer. The results of most studies suggest that KLF4 is a tumor suppressor. However, the functioning of KLF4 is regulated at many levels. These include regulation of transcription, alternative splicing, miRNA, post-translational modifications, subcellular localization, protein stability and interactions with other molecules. Simple experiments aimed at assaying transcript levels or protein levels fail to address this complexity and thus may deliver misleading results. Tumor subtypes are also important; for example, in prostate cancer KLF4 is highly expressed in indolent tumors where it impedes tumor progression, while it is absent from aggressive prostate tumors. KLF4 is important in regulating response to many known drugs, and it also plays a role in tumor microenvironment. More and more information is available about upstream regulators, downstream targets and signaling pathways associated with the involvement of KLF4 in cancer. Furthermore, KLF4 performs critical function in the overall regulation of tissue homeostasis, cellular integrity, and progression towards malignancy. Here we summarize and analyze the latest findings concerning this fascinating transcription factor.
The Ca2+-binding protein, S100A6, belongs to the S100 family. Binding of Ca2+ induces a conformational change, which causes an increase in the overall S100A6 hydrophobicity and allows it to interact with many targets. S100A6 is expressed in different normal tissues and in many tumors. Up to now it has been shown that S100A6 is involved in cell proliferation, cytoskeletal dynamics and tumorigenesis, and that it might have some extracellular functions. In this review, we summarize novel discoveries concerning S100A6 targets, its involvement in cellular signaling pathways, and presence in stem/progenitor cells, extracellular matrix and body fluids of diseased patients.
Morphogen-dependent epidermal-specific transacting factors have not been defined in vertebrates. We demonstrate that a member of the grainyhead transcription factor family, Grainyhead-like 1 (XGrhl1) is essential for ectodermal ontogeny in Xenopus laevis. Expression of this factor is restricted to epidermal cells. Moreover, XGrhl1 is regulated by the BMP4 signaling cascade. Disruption of XGrhl1 activity in vivo results in a severe defect in terminal epidermal differentiation, with inhibition of XK81A1 epidermal keratin gene expression, a key target of BMP4 signaling. Furthermore, transcription of the XK81A1 gene is modulated directly by binding of XGRHL1 to a promoter-localized binding motif that is essential for high-level expression. These results establish a novel developmental role for XGrhl1 as a crucial tissue-specific regulator of vertebrate epidermal differentiation.
Introduction: The prevalence of smoking among medical students indicates that studying medicine is an insufficient protection from tobacco use. The aim of the study was an analysis of medical students’ attitudes towards smoking at the first and sixth year of their studies. Material and methods: A questionnaire on tobacco smoking was distributed among medical students of the study year 2002–2008 at the first and sixth year of their studies. The questionnaire used on the sixth year students included additional questions designed to assess changes in their attitudes towards smoking during their studies, to ask their opinion of the teaching of diagnostics and treatment of tobacco dependence (TD), and to discover how they evaluated their knowledge of the issue. The numbers of students who participated at the two points of the study were 287 and 175 respectively. Results: Students in their sixth year significantly less frequently smoked cigarettes regularly than those starting their medical education (13% v. 21%; p = 0.022). However, 20% of smokers started smoking during their studies. The proportion of smokers saying they were not embarrassed by their smoking habit was significantly lower among sixth-year students compared to first-year students (31% v. 70%; p = 0.0006), as were the numbers who said they wanted to quit smoking (91% v. 61%). Those who wished to undergo treatment for TD (54% v. 22%) were significantly higher among sixth year students group (p = 0.013 and p = 0.001, respectively). More than half (57%) the sixth-year students claimed that they had no knowledge of the diagnostics and treatment of TD, or that their knowledge on this issue was poor or very poor. In the opinion of 43% of students, the medical curriculum was not a good source of knowledge on TD. Conclusions: Medical studies induce positively students’ attitudes towards smoking. However, a proportion of individuals start smoking during studies, which may suggest dominance of genetic influences on smoking initiation in this period of life. In sixth-year students’ opinion, medical studies are not a sufficient source of knowledge on TD.
Epidermal growth factor receptor (EGFR) is a central transmitter of mitogenic signals in epithelial cells; enhanced EGFR activity is observed in many tumors of epithelial origin. S100A6 is a small calcium-binding protein, characteristic mainly of epithelial cells and fibroblasts, strongly implicated in cell proliferation and upregulated in tumors. In this study, using biochemical assays along with immunohistochemical and immunocytochemical analysis of organotypic and standard cultures of HaCaT keratinocytes with S100A6 overexpression or knock-down, we have examined the effect of S100A6 on EGFR activity and downstream signaling. We found that HaCaT cells overexpressing S100A6 had enhanced EGFR, phospho EGFR, and phospho extracellular signal-regulated kinase 1/2 (pERK1/2) staining intensity and level coupled to higher signal transducer and activator of transcription 3 (STAT3) activity. Conversely, S100A6 knockdown cells had impaired EGFR signaling that could be enhanced by addition of recombinant S100A6 to the culture media. Altogether the results show that S100A6 may exert its proproliferative effects through activating EGFR.
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