p53 family members in myogenic differentiation and rhabdomyosarcoma development.
The p53 family comprises the tumor suppressor p53 and the structural homologs p63 and p73. How the three family members cooperate in tumor suppression remains unclear. Here, we report different but complementary functions of the individual members for regulating retinoblastoma protein (RB) function during myogenic differentiation. Whereas p53 transactivates the retinoblastoma gene, p63 and p73 induce the cyclin-dependent kinase inhibitor p57 to maintain RB in an active, hypophosphorylated state. DeltaNp73 inhibits these functions of the p53 family in differentiation control, prevents myogenic differentiation, and enables cooperating oncogenes to transform myoblasts to tumorigenicity. DeltaNp73 is frequently overexpressed in rhabdomyosarcoma and essential for tumor progression in vivo. These findings establish differentiation control as a key tumor suppressor activity of the p53 family.
Cam
Hakan
H
Molecular Tumor Biology Group, Rudolf-Virchow-Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, 97078 Würzburg, Germany.
Griesmann
Heidi
H
Beitzinger
Michaela
M
Hofmann
Lars
L
Beinoraviciute-Kellner
Rasa
R
Sauer
Markus
M
Hüttinger-Kirchhof
Nicole
N
Oswald
Claudia
C
Friedl
Peter
P
Gattenlöhner
Stefan
S
Burek
Christof
C
Rosenwald
Andreas
A
Stiewe
Thorsten
T
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000166:cytology* / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
D016159:Tumor Suppressor Protein p53