PUBLICATION
Differential regulation of p53 function by the N-terminal ΔNp53 and Δ113p53 isoforms in zebrafish embryos
- Authors
- Davidson, W.R., Kari, C., Ren, Q., Daroczi, B., Dicker, A.P., and Rodeck, U.
- ID
- ZDB-PUB-101018-4
- Date
- 2010
- Source
- BMC Developmental Biology 10: 102 (Journal)
- Registered Authors
- Dicker, Adam P.
- Keywords
- none
- MeSH Terms
-
- Animals
- Base Sequence
- Cell Line
- Embryo, Nonmammalian/anatomy & histology
- Embryo, Nonmammalian/physiology*
- Embryo, Nonmammalian/radiation effects
- Gene Expression Regulation, Developmental*/radiation effects
- Humans
- Molecular Sequence Data
- Protein Isoforms/genetics
- Protein Isoforms/metabolism*
- RNA Caps
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Radiation, Ionizing
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism*
- Zebrafish/anatomy & histology
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish/metabolism*
- PubMed
- 20929554 Full text @ BMC Dev. Biol.
Citation
Davidson, W.R., Kari, C., Ren, Q., Daroczi, B., Dicker, A.P., and Rodeck, U. (2010) Differential regulation of p53 function by the N-terminal ΔNp53 and Δ113p53 isoforms in zebrafish embryos. BMC Developmental Biology. 10:102.
Abstract
BACKGROUND: 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 (DeltaN/Delta40) or no transactivation domain (Delta133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish DeltaNp53 ortholog in the context of FLp53 and the zebrafish Delta133p53 ortholog (Delta113p53) coexpressed in the developing embryo.
RESULTS: We cloned the zebrafish DeltaNp53 isoform and determined that ionizing radiation increased expression of steady-state DeltaNp53 and Delta113p53 mRNA levels in zebrafish embryos. Ectopic DeltaNp53 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 DeltaNp53 and for DeltaNp53-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 DeltaNp53 overexpression. By contrast, forced Delta113p53 expression had little effect on DeltaNp53-dependent embryonal phenotypes. These functional attributes were shared between zebrafish and human DeltaNp53 orthologs ectopically expressed in zebrafish embryos. All 3 zebrafish isoforms could be coimmunoprecipitated with each other after transfection into Saos2 cells.
CONCLUSIONS: 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 Delta113p53, forced DeltaNp53 expression itself led to developmental defects which depended, in part, on p21 transactivation. In contrast to FLp53, the developmental abnormalities caused by DeltaNp53 were not counteracted by concomitant expression of Delta113p53.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping