Antonini, Dario (2011) Role of p63 in skin biology: its function in cell proliferation and differentiation. [Tesi di dottorato] (Unpublished)

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Item Type: Tesi di dottorato
Language: English
Title: Role of p63 in skin biology: its function in cell proliferation and differentiation
Creators:
CreatorsEmail
Antonini, Darioantonini@ceinge.unina.it
Date: 31 January 2011
Number of Pages: 110
Institution: Università degli Studi di Napoli Federico II
Istituzioni (extra): CEINGE  Biotecnologie Avanzate, TIGEM – Telethon Insitute of Genetics and Medicine
Department: Biochimica e biotecnologie mediche
Doctoral School: SEMM – European School of Molecular Medicine
PHD name: PhD in Molecular Medicine (Molecular Oncology or Human Genetics)
PHD cycle: 22
PHD Coordinator:
nameemail
Salvatore, Francescosalvator@unina.it
Tutor:
nameemail
Russo, Tommasorussot@dbbm.unina.it
Missero, Caterinamissero@ceinge.unina.it
Fusco, Alfredoalfusco@unina.it
Dotto, Gian Paolopaolo.dotto@unil.ch
Date: 31 January 2011
Number of Pages: 110
Uncontrolled Keywords: p63, skin, proliferation, differentiation
MIUR S.S.D.: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Additional Information: Ciclo IV/XXII, Curriculum Molecular Oncology, CEINGE
Date Deposited: 16 Feb 2011 13:29
Last Modified: 10 Dec 2014 09:45
URI: http://www.fedoa.unina.it/id/eprint/8448

Abstract

p63, a p53 family member, plays an essential role in epidermal development controlling several biological functions, some of which remain poorly understood. Using a global gene expression analysis, I contributed to the identification of novel downstream targets and signaling pathways regulated by p63. We firstly identified a set of genes not specifically expressed in epidermis (non-epidermal genes) that are indirectly suppressed by p63. In parallel, p63 sustains Bone Morphogenetic Protein (BMP) signaling by directly suppressing transcription of the inhibitory Smad7, and by inducing Bmp7. In the absence of p63, BMP signaling is compromised and leads to ectopic expression of the non-epidermal genes in vitro and in vivo. Reactivation of BMP signaling by exogenous stimuli suppresses ectopic expression of non-epidermal genes in the absence of p63. These data indicate that p63 prevents ectopic expression of non-epidermal genes by a mechanism involving activation of BMP signaling. In our genome-wide analysis we also observed that many cell cycle genes were positively regulated by p63. I found that loss of p63 in keratinocytes causes cell cycle arrest both in vitro and in vivo. Thus, I investigated how cell cycle genes are affected by p63. I identified a new mechanism through which p63 favors cell cycle progression repressing two members of a microRNA family: miR-34a and miR-34c. In the absence of p63, I observed increased levels of miR-34a and miR-34c in primary mouse keratinocytes and in mouse embryonic skin. p63 directly binds to p53-consensus sites in both miR-34a and miR-34c gene promoters and inhibits their activity. Keratinocytes are arrested in the G1-phase of the cell cycle in the absence of p63 and have reduced levels of two cell cycle regulators, cyclin D1 and cyclin-dependent kinase 4 (Cdk4), that are known targets of miR-34. Importantly, concomitant downregulation of miR-34a and miR-34c in the absence of p63 restores cell cycle progression and the expression of cyclin D1 and Cdk4. These data demonstrate that p63 sustains cell cycle progression in keratinocytes not only by previously defined mechanisms, such as repression of the CDK inhibitor p21 Cip1/Waf1, but also by directly repressing components of the miR-34 family. In conclusion, during my PhD program I uncovered two novel mechanisms through which p63 regulates cell cycle progression and tissue identity in epidermis.

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