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PMID: 11032820 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Essential role of NAT1/p97/DAP5 in embryonic differentiation and the retinoic acid pathway.

The EMBO journal ·Vol. 19 ·No. 20 ·2000-10-16 ·Pages 5533-41

Yamanaka S, Zhang XY, Maeda M, Miura K, Wang S, Farese RV, Iwao H, Innerarity TL

Abstract

NAT1/p97/DAP5 is a newly identified protein that shares homology with the translation initiation factor eIF4G. Studies in vitro and in transfected cells indicated that NAT1 might suppress global translation, thereby repressing cellular proliferation. Here we studied the functions of NAT1 in vivo by disrupting its gene in mice. NAT1(-/-) embryos died during gastrulation, indicating a crucial role for NAT1 in embryogenesis. Undifferentiated NAT1(-/-) embryonic stem cells were normal in morphology, proliferation, global translation and gene expression profile. However, NAT1(-/-) cells exhibited an impaired ability to differentiate: they were resistant to differentiation induced by retinoic acid, and teratomas derived from them consisted of undifferentiated and poorly differentiated tissues. The expression of retinoic acid-responsive genes, such as the cell-cycle inhibitor p21(WAF1), was selectively impaired in NAT1(-/-) cells. Transcription from synthetic retinoic acid-responsive elements was also impaired. These data demonstrated that this translation initiation factor homolog controls specific gene expression pathways required for cellular differentiation.

MeSH Terms
Animals Cell Division Cyclin-Dependent Kinase Inhibitor p21 Cyclins/genetics,metabolism Embryo, Mammalian/cytology,drug effects,metabolism Embryonic Induction/drug effects Embryonic and Fetal Development/genetics Fetal Death/genetics Gene Deletion Gene Expression Regulation, Developmental/drug effects Gene Targeting Genes, Essential/genetics Genes, Reporter Genotype Mice Mice, Knockout Peptide Initiation Factors/chemistry,deficiency,genetics,metabolism Protein Biosynthesis Response Elements/genetics Signal Transduction/drug effects Stem Cells/cytology,metabolism Teratoma/genetics,pathology Transcription, Genetic/drug effects,genetics Tretinoin/pharmacology
Chemicals
Cdkn1a protein, mouse Cyclin-Dependent Kinase Inhibitor p21 Cyclins Peptide Initiation Factors eukaryotic translational regulator p97 Tretinoin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Yamanaka S
Laboratory of Animal Molecular Technology, Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Ikoma 630-0101, Nara, Japan. shinyay@gtc.aist-nara.ac.jp
Zhang X Y
Maeda M
Miura K
Wang S
Farese R V
Iwao H
Innerarity T L
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.20.5533
Email
shinyay@gtc.aist-nara.ac.jp
Published
2000-10-16
Pages
5533-41
Language
English
Region
England
NLM ID
8208664
PMCID
PMC314019
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/19.20.5533 PMC Full Text View journal details
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