Portal de Periódicos da CAPES

Wherefore Art Thou, YY1?

2010; Elsevier BV; Volume: 131; Issue: 1 Linguagem: Inglês

10.1038/jid.2010.322

1523-1747

Wendy B. Bollag, Roni J. Bollag,

Plant Molecular Biology Research

In this issue, Taguchi et al. demonstrate that the transcription factor Yin Yang-1 (YY1) regulates proliferation in three-dimensional cultures of the HaCaT human keratinocyte cell line. HaCaT keratinocytes overexpressing YY1 form artificial epidermal constructs that are thicker than those produced from vector-transfected cells. RNA interference-mediated YY1 knockdown decreases the thickness of YY1-overexpressing constructs, indicating that YY1 mediates the thickening. In primary keratinocytes, overexpressed YY1 also inhibits differentiation marker expression induced by calcium, supporting the idea that YY1 is important in regulating epidermal structure and function. In this issue, Taguchi et al. demonstrate that the transcription factor Yin Yang-1 (YY1) regulates proliferation in three-dimensional cultures of the HaCaT human keratinocyte cell line. HaCaT keratinocytes overexpressing YY1 form artificial epidermal constructs that are thicker than those produced from vector-transfected cells. RNA interference-mediated YY1 knockdown decreases the thickness of YY1-overexpressing constructs, indicating that YY1 mediates the thickening. In primary keratinocytes, overexpressed YY1 also inhibits differentiation marker expression induced by calcium, supporting the idea that YY1 is important in regulating epidermal structure and function. The transcription factor Yin Yang-1 (YY1) is so named because this protein was first identified as a factor that in the absence of adenoviral E1A repressed transcription of the adenoviral-associated viral promoter but in the presence of E1A activated its transcription (reviewed in Gordon et al., 2006Gordon S. Akpyan G. Garban H. et al.Transcription factor YY1: structure, function, and therapeutic implications in cancer biology.Oncogene. 2006; 25: 1125-1142Crossref PubMed Scopus (582) Google Scholar). YY1, a member of the zinc-finger Gli-Krüppel family of transcription factors, seems to be expressed ubiquitously and conserved from Xenopus to humans, with a series of eight splice variants of unknown function in humans (Gordon et al., 2006Gordon S. Akpyan G. Garban H. et al.Transcription factor YY1: structure, function, and therapeutic implications in cancer biology.Oncogene. 2006; 25: 1125-1142Crossref PubMed Scopus (582) Google Scholar). The Drosophila homolog of YY1 is pleiohomeotic, a member of the polycomb group family of homeotic gene repressors (Affar et al., 2006Affar E.B. Gay F. Shi Y. et al.Essential dosage-dependent functions of the transcription factor yin yang 1 in late embryonic development and cell cycle progression.Mol Cell Biol. 2006; 26: 3565-3581Crossref PubMed Scopus (164) Google Scholar). YY1 is reported to regulate the expression of various genes (Gordon et al., 2006Gordon S. Akpyan G. Garban H. et al.Transcription factor YY1: structure, function, and therapeutic implications in cancer biology.Oncogene. 2006; 25: 1125-1142Crossref PubMed Scopus (582) Google Scholar; Shi et al., 1997Shi Y. Lee J.S. Galvin K.M. Everything you have ever wanted to know about Yin Yang 1.Biochim Biophys Acta. 1997; 1332: F49-F66Crossref PubMed Scopus (456) Google Scholar), in some cases activating and in others repressing gene transcription. Several models have been proposed to explain the mechanism by which YY1 exerts these effects; in many cases YY1 appears to interact directly with components of the transcription machinery and/or other transcription factors (Gordon et al., 2006Gordon S. Akpyan G. Garban H. et al.Transcription factor YY1: structure, function, and therapeutic implications in cancer biology.Oncogene. 2006; 25: 1125-1142Crossref PubMed Scopus (582) Google Scholar). In mice, a global lack of the YY1 gene results in embryonic (peri-implantation) lethality. Interestingly, Shi and colleagues used a combination of hypomorphic and floxed alleles to generate animals expressing 25, 50, or 75% of the normal amount of YY1 protein (Affar et al., 2006Affar E.B. Gay F. Shi Y. et al.Essential dosage-dependent functions of the transcription factor yin yang 1 in late embryonic development and cell cycle progression.Mol Cell Biol. 2006; 26: 3565-3581Crossref PubMed Scopus (164) Google Scholar). These investigators demonstrated dosage-dependent effects of YY1 gene/protein expression on embryogenesis, with about one half of the embryos having a YY1 level 25% of that of wild-type mice dying during late fetal development. The mice that survived until parturition weighed less than wild-type littermates (approximately 80% of the weight of the wild-type animals), appeared pale and slightly cyanotic, and died within a day of birth. Necropsies revealed that the lungs failed to inflate in these animals. The possibility of a skin phenotype was not investigated, although it is tempting to speculate, particularly in view of the work presented by Taguchi et al. in this issue, that closer examination might reveal epidermal abnormalities as well. In future studies, this floxed YY1 mouse model may prove useful in determining the role of YY1 in epidermal structure and function. YY1 has been reported to regulate cell cycle progression: a decrease in levels of YY1 using a hypomorphic allele as described above, ablation of a floxed gene by Cre recombinase, or RNA interference-mediated knockdown leads to a reduction in proliferation in mouse embryo fibroblasts and cervical carcinoma (HeLa) cells (Affar et al., 2010). Indeed, complete loss of the gene appears to block cytokinesis, and microarray analyses of reduced (25%) YY1-expressing compared with wild-type mouse embryo fibroblasts revealed an upregulation of 231 genes and a decrease in 293 genes (Affar et al., 2006Affar E.B. Gay F. Shi Y. et al.Essential dosage-dependent functions of the transcription factor yin yang 1 in late embryonic development and cell cycle progression.Mol Cell Biol. 2006; 26: 3565-3581Crossref PubMed Scopus (164) Google Scholar), many of which are known to be involved in modulating growth. Consistent with these findings, Taguchi et al., 2011Taguchi S. Kawachi Y. Ishitsuka Y. et al.Overexpression of the transcription factor Yin-Yang-1 suppresses differentiation of HaCaT cells in three-dimensional cell culture.J Invest Dermatol. 2011; 131: 37-45Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar demonstrate that overexpression of full-length YY1 in HaCaT human epidermal keratinocytes induces proliferation and results in a thickening of an artificial epidermis reconstituted from these cells. In addition, YY1 overexpression suppresses expression of several differentiation markers, including keratins 1 and 10, involucrin, and filaggrin, supporting YY1's reported ability to repress the promoter activity of the differentiation markers involucrin (Alvarez-Salas et al., 2005Alvarez-Salas L.M. Benitez-Hess M.L. Dipaola J.A. YY-1 and c-Jun transcription factors participate in the repression of the human involucrin promoter.Int J Oncol. 2005; 26: 259-266PubMed Google Scholar) and loricrin (Xu et al., 2004Xu X. Kawachi Y. Nakamura Y. et al.Yin-yang 1 negatively regulates the differentiation-specific transcription of mouse loricrin gene in undifferentiated keratinocytes.J Invest Dermatol. 2004; 123: 1120-1126Crossref PubMed Scopus (20) Google Scholar). It should be noted that the investigators use the HaCaT cell line, a spontaneously immortalized keratinocyte cell line generated from adult human skin under conditions of low calcium (0.2 mM)-containing medium and elevated temperature (38.5 °C). The HaCaT cells do not recapitulate normal differentiation entirely, in that the cells express differentiation markers but at the same time continue to proliferate in high-calcium medium (Boukamp et al., 1988Boukamp P. Petrissevska R.T. Breitkreuz D. et al.Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line.J Cell Biol. 1988; 106: 761-771Crossref PubMed Scopus (3464) Google Scholar). (Taguchi et al. also note a lack of loricrin immunoreactivity in the HaCaT-derived artificial epidermis.) Nevertheless, the results were replicated in two-dimensional primary cultures of mouse epidermal keratinocytes, in which overexpression of YY1 inhibited the elevated extracellular calcium concentration-induced expression of several differentiation markers (keratin 1, involucrin, and loricrin; Taguchi et al., 2011Taguchi S. Kawachi Y. Ishitsuka Y. et al.Overexpression of the transcription factor Yin-Yang-1 suppresses differentiation of HaCaT cells in three-dimensional cell culture.J Invest Dermatol. 2011; 131: 37-45Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Accordingly, the importance of YY1 in regulating epidermal keratinocyte function does not appear to be limited to a single species or to immortalized keratinocytes. A second caveat is that the artificial epidermal constructs used in this study were derived from a clonal population of YY1-overexpressing keratinocytes (Taguchi et al., 2011Taguchi S. Kawachi Y. Ishitsuka Y. et al.Overexpression of the transcription factor Yin-Yang-1 suppresses differentiation of HaCaT cells in three-dimensional cell culture.J Invest Dermatol. 2011; 131: 37-45Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). It remains possible that any observed differences in proliferation and/or thickness result from clonal variations rather than from overexpression of YY1. However, this concern is largely obviated by the results obtained with RNA interference. Thus, lentiviral short hairpin RNA-mediated knockdown of the overexpressed YY1 returns the artificial epidermis to a thickness similar to that of the control, and differentiation markers are re-expressed, suggesting that the differences observed are, in fact, due to overexpressed YY1, and providing evidence that YY1 promotes proliferation and inhibits differentiation of epidermal keratinocytes.The transcription factor YY1 regulates proliferation by keratinocytes as well as epidermal structure. The transcription factor YY1 regulates proliferation by keratinocytes as well as epidermal structure. A question that remains is whether YY1 is related to human skin disease. Accumulating evidence supports a role for YY1 in several human cancers, including various epithelial malignancies such as prostate, ovarian, breast, cervical, colon, and lung cancers (Castellano et al., 2009Castellano G. Torrisi E. Ligresti G. et al.The involvement of the transcription factor Yin Yang 1 in cancer development and progression.Cell Cycle. 2009; 8: 1367-1372Crossref PubMed Scopus (119) Google Scholar). Other members of the Gli-Krüppel family of transcription factors (e.g., Gli1 and Gli2) are involved in the development of several skin tumors, including basal cell carcinoma, basaloid follicular hamartoma, cylindroma, and trichoblastoma (Sheng et al., 2002Sheng H. Goich S. Wang A. et al.Dissecting the oncogenic potential of Gli2: deletion of an NH2-terminal fragment alters skin tumor phenotype.Cancer Res. 2002; 62: 5308-5316PubMed Google Scholar), and Gli-similar 1 (Glis1) expression is upregulated in psoriasis (Nakashani et al., 2006Nakashani G. Kim Y.S. Nakajima T. et al.Regulatory role for Krüppel-like zinc-finger protein Gli-similar 1 (Glis1) in PMA-treated and psoriatic epidermis.J Invest Dermatol. 2006; 126: 49-60Crossref PubMed Scopus (17) Google Scholar). Finally, Kawada et al. have demonstrated that YY1 functions with another transcription factor, Sp1, to transactivate the gene ATP2C1, which encodes for a Golgi-localized calcium ATPase (Kawada et al., 2005Kawada H. Nishiyama C. Takagi A. et al.Transcriptional regulation of ATP2C1 gene by Sp1 and YY1 and reduced function of its promoter in Hailey–Hailey disease keratinocytes.J Invest Dermatol. 2005; 124: 1206-1214Crossref PubMed Scopus (35) Google Scholar). Mutations in this gene and/or loss of protein expression result in Hailey–Hailey disease, an autosomal dominant blistering skin disease characterized by insufficient cell–cell adhesion among suprabasal keratinocytes. Because YY1, together with Sp1, increases the expression of ATP2C1, it seems possible that congenital deficiency of YY1 may contribute to the etiology of Hailey–Hailey disease in some patients. Therefore, additional studies are warranted in order to define the role and mechanism of action of YY1 in regulating keratinocyte structure and function.