CELL CYCLE 2016, VOL. 15, NO. 3, 313 http://dx.doi.org/10.1080/15384101.2015.1131528

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Cdc6: Skin in the carcinogenesis game Leonardo K. Teixeiraa and Steven I. Reedb a Program of Cellular Biology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil; bDepartment of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA

ARTICLE HISTORY Received 30 November 2015; Accepted 3 December 2015

Initiation of DNA duplication occurs through the assembly of multiple protein complexes onto replication origins (ORIs). In late M phase and early G1, ORC, CDC6, CDT1, and MCM2-7 proteins are sequentially assembled onto ORIs to form pre-replication complexes. The ATPase activity of the CDC6 protein is critical for this process. In vitro, overexpression of Cdc6 has been shown to be sufficient to induce DNA rereplication, to activate the DNA damage response, and to promote cellular transformation. Moreover, sustained Cdc6 expression has been observed in early stages of tumor development in humans.1,2 However, no mouse models have been described that directly address the role of Cdc6 in mammalian carcinogenesis in vivo. In a recent paper published in Cell Cycle, the group of Juan Mendez at the Spanish National Cancer Research Center (CNIO) describe a mouse model that harbors a Cdc6 transgene driven by the Keratin-5 promoter (the K5-Cdc6 mouse), leading to considerable Cdc6 overexpression in several tissues with stratified epithelia, but particularly the skin.3 Surprisingly, even though Cdc6 overexpression promoted an increased loading of MCM proteins onto the chromatin of keratinocytes, there was no increase in DNA replication or cell proliferation rates. This suggests that keratinocytes, and presumably other cell types, have evolved mechanisms that maintain cellular homeostasis in the face of gross imbalances of components of the replication machinery. One likely explanation in that excessive Cdc6mediated loading of MCM complexes is shunted into the formation of dormant origins, which only come into play during replication stress. Indeed, it has been shown that moderate depletion of MCM proteins leads specifically to a reduction of dormant origins and concomitant sensitivity to replication stress.4,5 In this regard, it would be interesting to investigate whether keratinocytes from K5-Cdc6 mice have an altered response to replication stress. The K5-Cdc6 mouse did not exhibit spontaneous skin carcinogenesis, but accelerated the formation of carcinogen-induced papillomas. These results indicate that deregulation of Cdc6 alone is not sufficient to induce skin tumor formation in the C57BL/6 background but, as suggested by its enhancement of

DMBA/TPA protocol-mediated tumorigenicity, may cooperate with other oncogenic events, in this case mutation of Ras. One possible explanation may be Cdc6-mediated downregulation of tumor suppressors p16Ink4a and p19Arf and the resulting bypass of cellular senescence, a crucial barrier to Ras-mediated tumorigenesis.6 Consistent with this idea, it has been shown that Cdc6 overexpression promotes repression of the INK4/ARF locus through the recruitment of histone deacetylases and the induction of locus heterochromatinization.7 Inappropriate expression of Cdc6 is observed in a number of different human cancers, as either overexpression in non-small cell lung carcinoma and mantle cell lymphoma, or downregulation in prostate cancer. However, it remains to be determined whether Cdc6 dysregulation actively contributes to carcinogenesis in these tumor subsets. It will therefore be interesting to investigate the consequences of transgene-based Cdc6 overexpression in the pulmonary epithelial and B lymphocyte lineages, as well as attenuation of Cdc6 expression in the context of mouse prostate carcinogenesis models.

Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.

References 1. Bartkova J, et al. Nature 2006; 444:633-7; PMID:17136093; http://dx. doi.org/10.1038/nature05268 2. Liontos M, et al. Cancer Res 2007; 67:10899-909; PMID:18006835; http://dx.doi.org/10.1158/0008-5472.CAN-07-2837 3. B ua S, et al. Cell Cycle 2015; 14(24):3897-3907; PMID: 26697840; http://dx.doi.org/10.1080/15384101.2015.1120919 4. Ge X, et al. Genes Dev 2007; 21:3331-41; PMID:18079179; http://dx. doi.org/10.1101/gad.457807 5. Ibarra A, et al. Proc Natl Acad Sci USA 2008; 105:8956-61; PMID:18579778; http://dx.doi.org/10.1073/pnas.0803978105 6. Serrano M, et al. Cell 1997; 88:593-602; PMID:9054499; http://dx.doi. org/10.1016/S0092-8674(00)81902-9 7. Gonzalez S, et al. Nature 2006; 440:702-6; PMID:16572177; http://dx. doi.org/10.1038/nature04585

CONTACT Steven I. Reed [email protected] News & Views to: B ua S, et al. Cell Cycle 2015; 14(24):3897–3907; PMID: 26697840; http://dx.doi.org/10.1080/15384101.2015.1120919 © 2016 Taylor & Francis

Cdc6: Skin in the carcinogenesis game.

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