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Mice defective in p53 nuclear localization signal 1 exhibit exencephaly.

ABSTRACT: p53 is a major suppressor of human malignancy. The protein levels and activity are tightly regulated in cells. Early experiments identified nuclear localization signal 1 (NLS1) as a regulator of p53 localization. We have generated mice bearing a mutation in p53 ( NLS1 ), designated p53 ( NLS1 ). Our experiments confirm a role for NLS1 in regulating p53 function. Murine embryonic fibroblasts generated from homozygous p53 ( NLS1 ) animals are partially defective in cell cycle arrest and do not respond to inhibitory signals from oncogenic Ras. In addition, p53-dependent apoptosis is abrogated in thymocytes. Contrary to predicted results, fibroblasts from homozygous p53 ( NLS1 ) animals have a greater rate of proliferation than p53-null cells. In addition, p53 ( NLS1 ) cells are more resistant to UV-induced death. Surprisingly, the homozygous p53 ( NLS1 ) animals exhibit embryonic and peri-natal lethality, with a significant portion of the animals developing exencephaly. Thus, p53 ( NLS1/NLS1 ) embryos exhibit a reduced viability relative to p53-null mice. These studies indicate that the NLS1 is a major regulator of p53 activity in vivo.

SUBMITTER: Regeling A

PROVIDER: S-EPMC4234151 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Mice defective in p53 nuclear localization signal 1 exhibit exencephaly.

Regeling Anouk A Armata Heather L HL Gallant Judy J Jones Stephen N SN Sluss Hayla K HK

Transgenic research 20101203 4

p53 is a major suppressor of human malignancy. The protein levels and activity are tightly regulated in cells. Early experiments identified nuclear localization signal 1 (NLS1) as a regulator of p53 localization. We have generated mice bearing a mutation in p53 ( NLS1 ), designated p53 ( NLS1 ). Our experiments confirm a role for NLS1 in regulating p53 function. Murine embryonic fibroblasts generated from homozygous p53 ( NLS1 ) animals are partially defective in cell cycle arrest and do not res ...[more]

PMID: 21127973

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Project description:Histone deacetylase 5 (HDAC5), a class IIa deacetylase, is a prominent regulator of cellular and epigenetic processes that underlie the progression of human disease, ranging from cardiac hypertrophy to cancer. Although it is established that phosphorylation mediates 14-3-3 protein binding and provides the essential link between HDAC5 nucleo-cytoplasmic shuttling and transcriptional repression, thus far only four phospho-acceptor sites have been functionally characterized. Here, using a combinatorial proteomics approach and phosphomutant screening, we present the first evidence that HDAC5 has at least 17 in vivo phosphorylation sites within functional domains, including Ser278 and Ser279 within the nuclear localization signal (NLS), Ser1108 within the nuclear export signal, and Ser755 in deacetylase domain. Global and targeted MS/MS analyses of NLS peptides demonstrated the presence of single (Ser278 and Ser279) and double (Ser278/Ser279) phosphorylations. The double S278/279A mutation showed reduced association with HDAC3, slightly decreased deacetylation activity, and significantly increased cytoplasmic localization compared with wild type HDAC5, whereas the S278A and S1108A phosphomutants were not altered. Live cell imaging revealed a deficiency in nuclear import of S278/279A HDAC5. Phosphomutant stable cell lines confirmed the cellular redistribution of NLS mutants and revealed a more pronounced cytoplasmic localization for the single S279A mutant. Proteomic analysis of immunoisolated S278/279A, S279A, and S259/498A mutants linked altered cellular localization to changes in protein interactions. S278/279A and S279A HDAC5 showed reduced association with the NCoR-HDAC3 nuclear corepressor complex as well as protein kinase D enzymes, which were potentiated in the S259/498A mutant. These results provide the first link between phosphorylation outside the known 14-3-3 sites and downstream changes in protein interactions. Together these studies identify Ser279 as a critical phosphorylation within the NLS involved in the nuclear import of HDAC5, providing a regulatory point in nucleo-cytoplasmic shuttling that may be conserved in other class IIa HDACs-HDAC4 and HDAC9.

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Mice defective in p53 nuclear localization signal 1 exhibit exencephaly.

Publications

Mice defective in p53 nuclear localization signal 1 exhibit exencephaly.

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