title: The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo.
abstract: The p53 tumor suppressor is a transcription factor that mediates varied cellular responses. The C terminus of p53 is subjected to multiple and diverse post-translational modifications. An attractive hypothesis is that differing sets of combinatorial modifications therein determine distinct cellular outcomes. To address this in vivo, a Trp53(ΔCTD/ΔCTD) mouse was generated in which the endogenous p53 is targeted and replaced with a truncated mutant lacking the C-terminal 24 amino acids. These Trp53(ΔCTD/ΔCTD) mice die within 2 wk post-partum with hematopoietic failure and impaired cerebellar development. Intriguingly, the C terminus acts via three distinct mechanisms to control p53-dependent gene expression depending on the tissue. First, in the bone marrow and thymus, the C terminus dampens p53 activity. Increased senescence in the Trp53(ΔCTD/ΔCTD) bone marrow is accompanied by up-regulation of Cdkn1 (p21). In the thymus, the C-terminal domain negatively regulates p53-dependent gene expression by inhibiting promoter occupancy. Here, the hyperactive p53(ΔCTD) induces apoptosis via enhanced expression of the proapoptotic Bbc3 (Puma) and Pmaip1 (Noxa). In the liver, a second mechanism prevails, since p53(ΔCTD) has wild-type DNA binding but impaired gene expression. Thus, the C terminus of p53 is needed in liver cells at a step subsequent to DNA binding. Finally, in the spleen, the C terminus controls p53 protein levels, with the overexpressed p53(ΔCTD) showing hyperactivity for gene expression. Thus, the C terminus of p53 regulates gene expression via multiple mechanisms depending on the tissue and target, and this leads to specific phenotypic effects in vivo.
authors.affiliation: Department of Oncological Sciences.
authors.forename: Pierre-Jacques
authors.initials: PJ
authors.lastname: Hamard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barthelery
authors.forename: Brandon
authors.initials: B
authors.lastname: Hogstad
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Mungamuri
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Tonnessen
authors.forename: Luis A
authors.initials: LA
authors.lastname: Carvajal
authors.forename: Emir
authors.initials: E
authors.lastname: Senturk
authors.forename: Virginia
authors.initials: V
authors.lastname: Gillespie
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: James J
authors.initials: JJ
authors.lastname: Manfredi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D016158:Genes, p53 / Q000235:genetics*; D048788:Growth and Development / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017384:Sequence Deletion / Q000235:genetics; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: C terminus; gene expression; hematopoiesis; mouse; p53; tissue specificity