title: p63 and p73 in tumor suppression and promotion.
abstract: The recent discovery of two genes, termed p63 and p73, encoding transcription factors highly homologous to p53 presents unexpected challenges and opportunities for the understanding and treatment of cancers. The questions raised are many but center on determining whether these new genes possess novel tumor suppressor functions, cooperate with p53, or impart oncogenic effects. At present there is considerable discord in the field concerning these concepts with some favoring a tumor suppressor role for the p53 family members and others an oncogenic influence. In support of a tumor suppressor role is the ability of p73 and p63 isoforms to transactivate p53 target genes and the large body of work linking p73, and to some extent p63, in apoptotic events in response to cellular stresses generally considered the purview of p53. More recently, p73 has been implicated in cell death following T cell activation, the response of cancers to chemotherapy, and finally, along with p63, to the function of p53 itself. Opposing this view is the fact that the p73 and p63 genes are rarely mutated in cancers and the stark absence of tumors in the p73 null mouse. Moreover, the high expression of dominant negative (dn) versions of the p73 and p63 proteins supports an anti-p53 function and therefore possibly an oncogenic effect. Indeed, the p63 gene is located in a region of chromosome three amplified in squamous cell carcinomas and the number of reports of dn-p63 overexpression in these diseases is increasing. This review will examine both sides of these arguments in an attempt to decipher common themes and to identify opportunities these genes represent for understanding tumorigenesis.
authors.affiliation: Department of Cell Biology, Harvard Medical School, USA. fmckeon@hms.harvard.edu
authors.forename: Frank D
authors.initials: FD
authors.lastname: McKeon
references.citation: Nat Genet. 2000 May;25(1):47-54
references.pmid: 10802655
references.citation: Cell. 1997 Feb 7;88(3):323-31
references.pmid: 9039259
references.citation: Nat Med. 1998 Jul;4(7):747-8
references.pmid: 9662346
references.citation: Mol Cell Biol. 1999 Feb;19(2):1438-49
references.pmid: 9891077
references.citation: Cancer Cell. 2003 Apr;3(4):403-10
references.pmid: 12726865
references.citation: Eur J Cancer. 1995;31A(4):538-41
references.pmid: 7576962
references.citation: Nature. 2000 Mar 2;404(6773):99-103
references.pmid: 10716451
references.citation: Biochem Biophys Res Commun. 1998 Jul 30;248(3):603-7
references.pmid: 9703973
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5462-7
references.pmid: 10805802
references.citation: Nature. 2002 Apr 4;416(6880):560-4
references.pmid: 11932750
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):479-84
references.pmid: 8552665
references.citation: Nat Genet. 2000 Dec;26(4):464-9
references.pmid: 11101847
references.citation: Cell. 2000 Mar 31;101(1):91-101
references.pmid: 10778859
references.citation: Nature. 1999 Jun 24;399(6738):814-7
references.pmid: 10391251
references.citation: Nature. 1992 Mar 19;356(6366):215-21
references.pmid: 1552940
references.citation: Apoptosis. 2001 Jun;6(3):173-82
references.pmid: 11388666
references.citation: Nature. 2000 Oct 5;407(6804):642-5
references.pmid: 11034214
references.citation: Nat Cell Biol. 2003 Jun;5(6):552-8
references.pmid: 12766778
references.citation: Cell. 2000 Mar 31;101(1):103-13
references.pmid: 10778860
references.citation: Nature. 2000 Oct 5;407(6804):645-8
references.pmid: 11034215
references.citation: Nature. 1997 Sep 11;389(6647):191-4
references.pmid: 9296498
references.citation: Cancer Cell. 2003 Apr;3(4):387-402
references.pmid: 12726864
references.citation: Cancer Res. 2001 May 15;61(10):4122-9
references.pmid: 11358835
references.citation: Nature. 1999 Jun 24;399(6738):734-5, 737
references.pmid: 10391235
references.citation: Mamm Genome. 1998 Nov;9(11):899-902
references.pmid: 9799841
references.citation: Nature. 1999 Jun 24;399(6738):806-9
references.pmid: 10391249
references.citation: Science. 2000 Jul 14;289(5477):304-6
references.pmid: 10894779
references.citation: Nature. 1999 Apr 22;398(6729):714-8
references.pmid: 10227294
references.citation: Nature. 1999 Jun 24;399(6738):809-13
references.pmid: 10391250
references.citation: Nat Rev Mol Cell Biol. 2000 Dec;1(3):199-207
references.pmid: 11252895
references.citation: Cell. 1997 Aug 22;90(4):809-19
references.pmid: 9288759
references.citation: Hum Pathol. 2003 Sep;34(9):850-6
references.pmid: 14562279
references.citation: Trends Genet. 2002 Feb;18(2):90-5
references.pmid: 11818141
references.citation: Mol Cell. 1998 Sep;2(3):305-16
references.pmid: 9774969
references.citation: Nat Med. 1998 Jul;4(7):839-43
references.pmid: 9662378