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P53 N-terminal phosphorylation: a defining layer of complex regulation.

ABSTRACT: The p53 tumor suppressor is a critical component of the cellular response to stress. As it can inhibit cell growth, p53 is mutated or functionally inactivated in most tumors. A multitude of protein-protein interactions with transcriptional cofactors are central to p53-dependent responses. In its activated state, p53 is extensively modified in both the N- and C-terminal regions of the protein. These modifications, especially phosphorylation of serine and threonine residues in the N-terminal transactivation domain, affect p53 stability and activity by modulating the affinity of protein-protein interactions. Here, we review recent findings from in vitro and in vivo studies on the role of p53 N-terminal phosphorylation. These modifications can either positively or negatively affect p53 and add a second layer of complex regulation to the divergent interactions of the p53 transactivation domain.

SUBMITTER: Jenkins LM

PROVIDER: S-EPMC3499055 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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p53 N-terminal phosphorylation: a defining layer of complex regulation.

Jenkins Lisa M Miller LM Durell Stewart R SR Mazur Sharlyn J SJ Appella Ettore E

Carcinogenesis 20120412 8

The p53 tumor suppressor is a critical component of the cellular response to stress. As it can inhibit cell growth, p53 is mutated or functionally inactivated in most tumors. A multitude of protein-protein interactions with transcriptional cofactors are central to p53-dependent responses. In its activated state, p53 is extensively modified in both the N- and C-terminal regions of the protein. These modifications, especially phosphorylation of serine and threonine residues in the N-terminal trans ...[more]

PMID: 22505655

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Project description:The p53 protein family coordinates stress responses of cells and organisms. Alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N- and C-termini which are differentially expressed in normal and malignant cells. The human N-terminal p53 variants contain either the full-length (FL), or a truncated (?N/?40) or no transactivation domain (?133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish ?Np53 ortholog in the context of FLp53 and the zebrafish ?133p53 ortholog (?113p53) coexpressed in the developing embryo.We cloned the zebrafish ?Np53 isoform and determined that ionizing radiation increased expression of steady-state ?Np53 and ?113p53 mRNA levels in zebrafish embryos. Ectopic ?Np53 expression by mRNA injection caused hypoplasia and malformation of the head, eyes and somites, yet partially counteracted lethal effects caused by concomitant expression of FLp53. FLp53 expression was required for developmental aberrations caused by ?Np53 and for ?Np53-dependent expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A, p21, Cip1, WAF1). Knockdown of p21 expression markedly reduced the severity of developmental malformations associated with ?Np53 overexpression. By contrast, forced ?113p53 expression had little effect on ?Np53-dependent embryonal phenotypes. These functional attributes were shared between zebrafish and human ?Np53 orthologs ectopically expressed in zebrafish embryos. All 3 zebrafish isoforms could be coimmunoprecipitated with each other after transfection into Saos2 cells.Both alternative N-terminal p53 isoforms were expressed in developing zebrafish in response to cell stress and antagonized lethal effects of FLp53 to different degrees. However, in contrast to ?113p53, forced ?Np53 expression itself led to developmental defects which depended, in part, on p21 transactivation. In contrast to FLp53, the developmental abnormalities caused by ?Np53 were not counteracted by concomitant expression of ?113p53.

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P53 N-terminal phosphorylation: a defining layer of complex regulation.

Publications

p53 N-terminal phosphorylation: a defining layer of complex regulation.

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