Role of p63 in skin biology: its function in cell proliferation and differentiation

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

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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.

Tipologia di documento:Tesi di dottorato
Altre informazioni:EUROPEAN SCHOOL OF MOLECULAR MEDICINE - SEMM - SEDE DI NAPOLI UNIVERSITA’ DEGLI STUDI DI NAPOLI “FEDERICO II” Ph.D. in Molecular Medicine – Ciclo IV/XXII Molecular Oncology CEINGE
Parole chiave:p63, skin, proliferation, differentiation
Settori scientifico-disciplinari MIUR:Area 05 Scienze biologiche > BIO/11 BIOLOGIA MOLECOLARE
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Salvatore, Francescosalvator@unina.it
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Russo, Tommasorussot@dbbm.unina.it
Missero, Caterinamissero@ceinge.unina.it
Fusco, Alfredoalfusco@unina.it
Dotto, Gian Paolopaolo.dotto@unil.ch
Stato del full text:Accessibile
Data:31 Gennaio 2011
Numero di pagine:110
Istituzione:Università degli studi di Napoli Federico II
Dipartimento o Struttura:Biochimica e biotecnologie mediche
Tipo di tesi:Dottorato
Stato dell'Eprint:Inedito
Scuola di dottorato:Medicina molecolare
Denominazione del dottorato:Molecular Medicine
Ciclo di dottorato:22
Numero di sistema:8448
Depositato il:16 Febbraio 2011 14:29
Ultima modifica:23 Giugno 2011 12:32

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