Identification and functional characterization of two new transcriptional variants of the human p63 gene.
p63 belongs to a family of transcription factors, which, while demonstrating striking conservation of functional domains, regulate distinct biological functions. Its principal role is in the regulation of epithelial commitment, differentiation and maintenance programs, during embryogenesis and in adult tissues. The p63 gene has a complex transcriptional pattern, producing two subclasses of N-terminal isoforms (TA and DeltaN) which are alternatively spliced at the C-terminus. Here, we report the identification of two new C-terminus p63 variants, we named p63 delta and epsilon, that increase from 6 to 10 the number of the p63 isoforms. Expression analysis of all p63 variants demonstrates a tissue/cell-type-specific nature of p63 alternative transcript expression, probably related to their different cellular functions. We demonstrate that the new p63 variants as DeltaN isoforms are active as transcription factors as they have nuclear localization and can modulate the expression of p63 target genes. Moreover, we report that, like DeltaNp63alpha, DeltaNp63delta and epsilon sustain cellular proliferation and that their expression decreases during keratinocyte differentiation, suggesting their involvement in this process. Taken together, our results demonstrate the existence of novel p63 proteins whose expression should be considered in future studies on the roles of p63 in the regulation of cellular functions.
Mangiulli
Marina
M
Dipartimento di Biochimica e Biologia Molecolare E. Quagliariello, Università degli Studi di Bari, via Orabona 4, 70126 Bari, Italy.
Valletti
Alessio
A
Caratozzolo
Mariano Francesco
MF
Tullo
Apollonia
A
Sbisà
Elisabetta
E
Pesole
Graziano
G
D'Erchia
Anna Maria
AM
D000465:Algorithms; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000032:analysis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D009687:Nuclear Proteins; D020033:Protein Isoforms; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
Oncogene. 2007 Aug 9;26(36):5169-83
17334395
Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W440-3
16845044
Cancer Res. 2005 Mar 15;65(6):2314-20
15781645
Mol Carcinog. 2007 Aug;46(8):716-24
17477357
Nature. 1999 Apr 22;398(6729):708-13
10227293
J Invest Dermatol. 2007 May;127(5):1175-86
17159913
BMC Mol Biol. 2007 Sep 28;8:85
17903252
J Dermatol Sci. 2004 Feb;34(1):3-9
14757276
Nature. 2002 Apr 4;416(6880):560-4
11932750
Mol Cell. 1998 Sep;2(3):305-16
9774969
Nature. 1992 Mar 19;356(6366):215-21
1552940
Cell Death Differ. 2006 Jun;13(6):1037-47
16601749
Genes Dev. 2006 Nov 15;20(22):3185-97
17114587
Cell Cycle. 2007 Feb 1;6(3):262-8
17224651
Cancer Cell. 2005 Apr;7(4):363-73
15837625
Nature. 2000 Mar 2;404(6773):99-103
10716451
Biochem Biophys Res Commun. 2006 Apr 21;342(4):1356-60
16516862
Cell Cycle. 2006 Jan;5(2):205-12
16410722
Mol Cell Biol. 2003 Apr;23(7):2264-76
12640112
Nature. 1999 Apr 22;398(6729):714-8
10227294
Cell Death Differ. 2006 Jun;13(6):962-72
16601753
Bioinformatics. 2008 May 15;24(10):1300-4
18388144
Cell Cycle. 2006 Apr;5(7):750-8
16582625
Mol Cell Biol. 2002 Dec;22(24):8601-11
12446779
J Pathol. 2007 Dec;213(4):384-91
17935121
Exp Cell Res. 2006 Apr 1;312(6):695-706
16406339
Mol Cell Biol. 2002 Dec;22(24):8659-68
12446784
J Biol Chem. 2006 Feb 3;281(5):2533-42
16319057
Mol Cell. 2002 Nov;10(5):995-1005
12453409
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8435-40
16714381