Loss of function of def selectively up-regulates Delta113p53 expression to arrest expansion growth of digestive organs in zebrafish.
Transcription factor p53 forms a network with associated factors to regulate the cell cycle and apoptosis in response to environmental stresses. However, there is currently no direct genetic evidence to show if or how the p53 pathway functions during organogenesis. Here we present evidence to show that the zebrafish def (digestive-organ expansion factor) gene encodes a novel pan-endoderm-specific factor. A loss-of-function mutation in def confers hypoplastic digestive organs and selectively up-regulates the expression of Delta113p53, counterpart to a newly identified isoform of p53 produced by an alternative internal promoter in intron 4 of the p53 gene in human. The increased Delta113p53 expression is limited to within the mutant digestive organs, and this increase selectively induces the expression of p53-responsive genes to trigger the arrest of the cell cycle but not apoptosis, resulting in compromised organ growth in the mutant. Our data demonstrate that, while induction of expression of p53 and/or its isoforms is crucial to suppress abnormal cell growth, Delta113p53 is tightly regulated by an organ/tissue-specific factor Def, especially during organogenesis, to prevent adverse inhibition of organ/tissue growth.
Chen
Jun
J
Laboratory of Functional Genomics, Laboratory of Molecular and Developmental Immunology, Laboratory of Control of p53 Pathway, Institute of Molecular and Cell Biology, Proteos, Singapore 138673.
Ruan
Hua
H
Ng
Sok Meng
SM
Gao
Chuan
C
Soo
Hui Meng
HM
Wu
Wei
W
Zhang
Zhenhai
Z
Wen
Zilong
Z
Lane
David P
DP
Peng
Jinrong
J
D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D004064:Digestive System / Q000254:growth & development; D004625:Embryo, Nonmammalian; D004707:Endoderm; D038081:Organogenesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000502:physiology
D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C507219:digestive-organ expansion factor, zebrafish