Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23.
Phosphorylation of the p53 tumor suppressor at Ser20 (murine Ser23) has been proposed to be critical for disrupting p53 interaction with its negative regulator, MDM2, and allowing p53 stabilization. To determine the importance of Ser23 for the function of p53 in vivo, we generated a mouse in which the endogenous p53 locus was targeted to replace Ser23 with alanine. We show that, in mouse embryonic fibroblasts generated from Ser23 mutant mice, Ser23 mutation did not dramatically reduce IR-induced p53 protein stabilization or p53-dependent cell cycle arrest. However, in Ser23 mutant thymocytes and in the developing cerebellum, p53 stabilization following IR was decreased and resistance to apoptosis was observed. Homozygous Ser23 mutant animals had a reduced lifespan, but did not develop thymic lymphomas or sarcomas that are characteristic of p53-/- mice. Instead, Ser23 mutant animals died between 1 and 2 years with tumors that were most commonly of B-cell lineage. These data support an important role for Ser20/23 phosphorylation in p53 stabilization, apoptosis and tumor suppression.
MacPherson
David
D
MIT Department of Biology and Center for Cancer Research, Cambridge, MA, USA.
Kim
Jungho
J
Kim
Teresa
T
Rhee
Byung Kirl
BK
Van Oostrom
Conny Th M
CT
DiTullio
Richard A
RA
Venere
Monica
M
Halazonetis
Thanos D
TD
Bronson
Roderick
R
De Vries
Annemieke
A
Fleming
Mark
M
Jacks
Tyler
T
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002478:Cells, Cultured; D002531:Cerebellum / Q000196:embryology / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006720:Homozygote; D007259:Infrared Rays; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D017354:Point Mutation; D012694:Serine / Q000737:chemistry / Q000235:genetics; D015996:Survival Rate; D013950:Thymus Gland / Q000196:embryology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology
D016159:Tumor Suppressor Protein p53; D012694:Serine