Abstract:
:The retinoblastoma gene product (pRb) controls proliferation and differentiation processes in stratified epithelia. Importantly, and in contrast to other tissues, Rb deficiency does not lead to spontaneous skin tumor formation. As the cyclin-dependent kinase inhibitor p21 regulates proliferation and differentiation in the absence of pRb, we analyzed the consequences of deleting p21 in pRb-ablated stratified epithelia (hereafter pRb(ΔEpi);p21-/-). These mice display an enhancement of the phenotypic abnormalities observed in pRb(ΔEpi) animals, indicating that p21 partially compensates pRb absence. Remarkably, pRb(ΔEpi);p21-/- mice show an acute skin inflammatory phenotype and develop spontaneous epithelial tumors, particularly affecting tongue and oral tissues. Biochemical analyses and transcriptome studies reveal changes affecting multiple pathways, including DNA damage and p53-dependent signaling responses. Comparative metagenomic analyses, together with the histopathological profiles, indicate that these mice constitute a faithful model for human head and neck squamous cell carcinomas. Collectively, our findings demonstrate that p21, in conjunction with pRb, has a central role in regulating multiple epithelial processes and orchestrating specific tumor suppressor functions.
journal_name
Oncogenejournal_title
Oncogeneauthors
Saiz-Ladera C,Lara MF,Garín M,Ruiz S,Santos M,Lorz C,García-Escudero R,Martínez-Fernández M,Bravo A,Fernández-Capetillo O,Segrelles C,Paramio JMdoi
10.1038/onc.2013.417subject
Has Abstractpub_date
2014-09-11 00:00:00pages
4599-4612issue
37eissn
0950-9232issn
1476-5594journal_volume
33pub_type
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