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P63 and P73, the Ancestors of P53 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press p63 and p73, the Ancestors of p53 V. Do¨ tsch1, F. Bernassola2, D. Coutandin1, E. Candi2, and G. Melino2,3 1Institute of Biophysical Chemistry, Goethe University, Frankfurt am Main, Germany 2IDI-IRCCS Biochemistry Laboratory, Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy 3Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Lancaster Road, P.O. Box 138, Leicester LE1 9HN, United Kingdom Correspondence: [email protected] p73 and p63 are two homologs of the tumor suppressive transcription factor p53. Given the high degree of structural similarity shared by the p53 family members, p73 and p63 can bind and activate transcription from the majority of the p53-responsive promoters. Besides over- lapping functions shared with p53 (i.e., induction of apoptosis in response to cellular stress), the existence of extensive structural variability within the family determines unique roles for p63 and p73. Their crucial and specific functions in controlling development and differentiation are well exemplified by the p63 and p73 knockout mouse phenotypes. Here, we describe the contribution of p63 and p73 to human pathology with emphasis on their roles in tumorigenesis and development. 63 (Yang et al. 1998) and p73 (Jost et al. an alternative promoter located in the third in- p1997; Kaghad et al. 1997) are two structural tron, both p63 and p73 exist as multiple protein and functional homologs of the tumor sup- variants, displaying similar or antagonistic ac- pressing transcription factor p53. As a result tivities. The full-length isoforms (TAp63 and of sharing similar domain architecture and TAp73), containing a transactivation domain sequence identity with p53, p73 and p63 can (TAD), generally behave similarly to p53 in form oligomers, bind DNA, transactivate p53- terms of overlapping target promoters and responsive genes, and mediate cell cycle arrest, biological functions. Among the TA variants, cellular senescence, and apoptosis in response alternative splicing events generate proteins to DNA damage (Jost et al. 1997; Yang et al. displaying different transactivation capacity. 1998; De Laurenzi et al. 1998; Melino et al. The usage of the alternative promoter produces 2004; Keyes et al. 2005) (See Fig. 1). amino-terminally truncated DN isoforms, Because of splicing events occurring at the which are devoid of the TADand therefore tran- carboxy-terminal end, and to the presence of scriptionally inactive. As a consequence, these Editors: Arnold J. Levine and David P. Lane Additional Perspectives on The p53 Family available at www.cshperspectives.org Copyright # 2010 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a004887 Cite this article as Cold Spring Harb Perspect Biol 2010;00:a004887 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press V. Do¨ tsch et al. ABCell-cycle arrest Apoptosis Development C TA PR DBD OD p53 +++ +++ – Cancer p53 N C minimal DNp53 ?? ++ 22% 60% 38% TA PR DBD OD PR SAM TAp63 ++ + +++ Epidermal p63 N C ΔNp63 – – + lethal 30% 63% 38% TAp73 ++ ++ +++ Neural TA PR DBD OD PR SAM p73 N C ΔNp73 – – ++ severe Figure 1. Schematic representation of the protein modular structure of the p53 family members. (A) The p53 family includes three genes that encode p53, p73, and p63. The overall domain structure of p53, p73, and p63 is conserved and consists of an amino-terminal transactivation domain (TAD), a central DNA binding domain (DBD) and a carboxy-terminal oligomerization domain (OD). The longest a isoform of p73 and p63 contains a sterile alpha motif (SAM), a putative protein–protein interaction domain found in many signaling proteins and transcription factors. Identity shared by p73 and p63 with p53 is indicated. (B) Simplified classification of the functions of the p53 family members. Members of this family are involved in similar as well as in unique cellular functions, with the most important role of p63 and p73 being regulation of differentiation and development. Their crucial and specific functions in controlling development and differentiation are well exemplified by the p63 and p73 knockout mouse developmental phenotypes (C). isoforms act as inhibitors of the active family STRUCTURAL FEATURES OF THE FAMILY members. Hence, the structural complexity MEMBERS that distinguishes these proteins, confers molec- ular flexibility, and determines a corresponding The p53 family members are modular proteins functional diversity within the family. with a similar basic structure, which is sche- As a consequence, although p63 and p73 matically depicted in Figure 1. There are three share many functional properties of p53, and major domains, which are highly conserved cooperate with p53 in the regulation of tum- between the family members. The TAD is the origenesis, in the absence of stress, the most least conserved with 22% identity between p63 important role of these p53 family members is and p53 and 30% between p73 and p53. The regulation of differentiation and development. core DNA binding domain (DBD) of p63 and Indeed, both p63 and p73 exhibit distinct and p73 are 60% and 63% identical with p53 respec- unique biological functions. p63 plays a relevant tively. In addition, the residues of p53 that role in the development of squamous epithelia directly interact with DNA are identical in p63 and their derivatives, while p73 is indispensable and p73. Consequently, both p63 and p73 can for neuronal differentiation and the develop- bind to canonical p53 DNA-binding sites and ment of nervous and olfactory systems. Consis- activate transcription from p53-responsive pro- tently, p63 and p73 deficient mice manifest moters, thus inducing cell cycle arrest, apopto- severe limb truncations, absence of skin, hair, sis and cellular senescence (Jost et al. 1997; Yang teeth, mammary, lachrymal, and salivary glands et al. 1998; De Laurenzi et al. 1998, Melino et al. (Mills et al. 1999; Yang et al. 1999) and complex 2004; Keyes et al. 2005). The carboxy-terminal defects in neuronal development (Yang et al. oligomerization domain (OD) of p53 is 38% 2000; Pozniak et al. 2000), respectively. As identical with p63 and p73. a result, imbalance within the p53 protein p63 and p73 exist as multiple functionally family contributes to a significant proportion diverse proteins that originate from a combi- of congenital developmental abnormalities in nation of alternative promoter usage and alter- humans. native splicing (De Laurenzi et al. 1998; De 2 Cite this article as Cold Spring Harb Perspect Biol 2010;00:a004887 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press p63 and p73, the Ancestors of p53 Laurenzi et al. 1999; Grob et al. 2001). The p63 thermodynamically most stable form, suggest- and p73 genes encode several distinct protein ing that such heterocomplexes might exist in isoforms generated by alternative splicing at cells as well. Interestingly, Rocco et al. showed the carboxy-terminal, giving rise to three p63 that the majority of TAp73b is physically bound variants (a2g) (Yang et al. 1998) and at least to DNp63a in JHU 029 cells, a cell line derived six different p73 terminal variants (a2z) (De from head and neck squamous cell carcinoma Laurenzi et al. 1998; De Laurenzi et al. 1999). (Rocco et al. 2006). These examples show that Interestingly, the p53 gene has recently been the structural complexity of the p53 family and found to also generate multiple protein variants the reciprocal regulatory networks cause a com- as a result of alternative splicing (Bourdon et al. plicated interplay between the family members 2005). The carboxy-terminal isoforms differ in and their isoforms. their ability to transactivate gene expres- Full-length and truncated isoforms of the sion (Zhu et al. 1998; De Laurenzi et al. 1999; p53 family generally exhibit reciprocal biologi- Lee and La Thangue 1999; Shimada et al. cal functions: truncated isoforms support pro- 1999). The full-length proteins (denoted as a- liferation while TA variants promote cell cycle isoforms) of p63 and p73 contain a carboxy-ter- arrest, cellular senescence and apoptosis. How- minal sterile a-motif (SAM) domain, involved ever, the activity of p63 and p73 proteins may in protein–protein interaction, and a transcrip- also depend on the intracellular context. As an tion inhibition domain (TID), that decreases example, even though ectopic expression of their transcriptional activity (Serber et al. TAp73b suppresses growth, this isoform can 2002; Straub et al. 2009) by enforcing a closed synergize with the proto-oncogene c-Jun to pro- conformation through the interaction with the mote cellular survival (Vikhanskaya et al. 2007). amino-terminal transactivation domain. Hence, the existence of p53 family proteins with Additionally, the p63 and p73 genes have two opposing activity implies that the balance of distinct promoters; the first promoter (P1) yields various isoforms may determine cell fate. a full-length protein possessing an amino- terminal TAD (TA isoforms), the second pro- EVOLUTION OF THE p53 FAMILY MEMBERS moter (P2), located within intron 3, gives rise to amino-terminally truncated proteins (DN Members of the p53 protein family are not only isoforms). The latter lack the amino-terminal found in vertebrates but also in many inverte- TAD and, as a result, they act as dominant brate species including mollusks, insects, and negative inhibitors of p53 and the full-length worms. Recent structure determinations of the TAvariants (Grob et al. 2001; Stiewe et al. 2002; DBD as well as of the OD of different members Nakagawa et al. 2002; Kartasheva et al. 2002). of this protein family have started to shed some In addition, several other amino-terminally light onto the evolutionary path of p53 and its truncated p73 isoforms initiating at different homologs. All members of the p53 protein ATGs have been described.
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