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PMID: 8183928 Published · ppublish English Journal Article

Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 91 ·No. 10 ·1994-05-10 ·Pages 4441-5

Jefferies HB, Reinhard C, Kozma SC, Thomas G

Abstract

The immunosuppressant rapamycin blocks p70s6k/p85s6k activation and phosphorylation of 40S ribosomal protein S6 in Swiss 3T3 cells. The same net result is obtained when the macrolide is added 3 hr after serum stimulation. In stimulated cells p70s6k/p85s6k inactivation is achieved within minutes, whereas S6 dephosphorylation requires 1-2 hr, supporting the concept that S6 dephosphorylation results from kinase inactivation. In parallel, rapamycin treatment causes a small, but significant, reduction in the initiation rate of protein synthesis, as measured both by [35S]methionine incorporation into protein and by recruitment of 80S ribosomes into polysomes. More striking, analysis of individual mRNA transcripts revealed that rapamycin selectively suppresses the translation of a family of mRNAs that is characterized by a polypyrimidine tract immediately after their N7-methylguanosine cap, a motif that can act as a translational modulator. This family includes transcripts for ribosomal proteins, elongation factors of protein synthesis, and proteins of as-yet-unknown function. The results imply that (i) 40S ribosomes containing phosphorylated S6 may selectively recognize this motif or proteins which bind to it and (ii) rapamycin may inhibit cell growth by blocking S6 phosphorylation and, thus, translation of these mRNAs.

MeSH Terms
3T3 Cells Actins/biosynthesis Animals Immunosuppressive Agents/pharmacology Methionine/metabolism Mice Molecular Sequence Data Oligonucleotide Probes Peptide Elongation Factor 1 Peptide Elongation Factors/biosynthesis Phosphorylation Polyenes/pharmacology Polyribosomes/metabolism Protein Biosynthesis/drug effects Pyrimidines RNA, Messenger/biosynthesis,chemistry,metabolism Ribosomal Protein S6 Ribosomal Proteins/drug effects,metabolism Sirolimus Transcription, Genetic
Chemicals
Actins Immunosuppressive Agents Oligonucleotide Probes Peptide Elongation Factor 1 Peptide Elongation Factors Polyenes Pyrimidines RNA, Messenger Ribosomal Protein S6 Ribosomal Proteins Methionine Sirolimus
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Jefferies H B
Friedrich Miescher Institute, Basel, Switzerland.
Reinhard C
Kozma S C
Thomas G
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.91.10.4441
Published
1994-05-10
Pages
4441-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC43801
Subset
IM
Databases
GENBANK
M76131, X03765, X13661
External Links
PubMed source DOI: 10.1073/pnas.91.10.4441 PMC Full Text View journal details
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