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PMID: 9822608 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase.

The EMBO journal ·Vol. 17 ·No. 22 ·1998-11-16 ·Pages 6649-59

Shima H, Pende M, Chen Y, Fumagalli S, Thomas G, Kozma SC

Abstract

Recent studies have shown that the p70(s6k)/p85(s6k) signaling pathway plays a critical role in cell growth by modulating the translation of a family of mRNAs termed 5'TOPs, which encode components of the protein synthetic apparatus. Here we demonstrate that homozygous disruption of the p70(s6k)/p85(s6k) gene does not affect viability or fertility of mice, but that it has a significant effect on animal growth, especially during embryogenesis. Surprisingly, S6 phosphorylation in liver or in fibroblasts from p70(s6k)/p85(s6k)-deficient mice proceeds normally in response to mitogen stimulation. Furthermore, serum-induced S6 phosphorylation and translational up-regulation of 5'TOP mRNAs were equally sensitive to the inhibitory effects of rapamycin in mouse embryo fibroblasts derived from p70(s6k)/p85(s6k)-deficient and wild-type mice. A search of public databases identified a novel p70(s6k)/p85(s6k) homolog which contains the same regulatory motifs and phosphorylation sites known to control kinase activity. This newly identified gene product, termed S6K2, is ubiquitously expressed and displays both mitogen-dependent and rapamycin-sensitive S6 kinase activity. More striking, in p70(s6k)/p85(s6k)-deficient mice, the S6K2 gene is up-regulated in all tissues examined, especially in thymus, a main target of rapamycin action. The finding of a new S6 kinase gene, which can partly compensate for p70(s6k)/p85(s6k) function, underscores the importance of S6K function in cell growth.

MeSH Terms
Amino Acid Sequence Animals Base Sequence Cloning, Molecular DNA Primers DNA, Complementary Embryo, Mammalian/cytology Embryonic and Fetal Development/genetics Fibroblasts/cytology Mice Mice, Mutant Strains Molecular Sequence Data Phenotype Phosphorylation Ribosomal Protein S6 Kinases/chemistry,genetics,metabolism Sequence Homology, Amino Acid
Chemicals
DNA Primers DNA, Complementary Ribosomal Protein S6 Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Shima H
Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Pende M
Chen Y
Fumagalli S
Thomas G
Kozma S C
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/17.22.6649
Published
1998-11-16
Pages
6649-59
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1171010
Subset
IM
Databases
GENBANK
AJ007938
External Links
PubMed source DOI: 10.1093/emboj/17.22.6649 PMC Full Text View journal details
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