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Molecular and Cellular Biology, April 2004, p. 3112-3124, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3112-3124.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

S6K1-/-/S6K2-/- Mice Exhibit Perinatal Lethality and Rapamycin-Sensitive 5'-Terminal Oligopyrimidine mRNA Translation and Reveal a Mitogen-Activated Protein Kinase-Dependent S6 Kinase Pathway

Mario Pende,1,2* Sung Hee Um,1 Virginie Mieulet,2 Melanie Sticker,1 Valerie L. Goss,3 Jurgen Mestan,4 Matthias Mueller,4 Stefano Fumagalli,1 Sara C. Kozma,1 and George Thomas1*

Friedrich Miescher Institute for Biomedical Research, 4058 Basel,1 Novartis Pharma AG, 4057 Basel, Switzerland,4 INSERM 584, Hormone Targets, 75015 Paris, France,2 Cell Signaling Technology, Beverly, Massachusetts 019153

Received 18 July 2003/ Returned for modification 18 September 2003/ Accepted 14 January 2004

Activation of 40S ribosomal protein S6 kinases (S6Ks) is mediated by anabolic signals triggered by hormones, growth factors, and nutrients. Stimulation by any of these agents is inhibited by the bacterial macrolide rapamycin, which binds to and inactivates the mammalian target of rapamycin, an S6K kinase. In mammals, two genes encoding homologous S6Ks, S6K1 and S6K2, have been identified. Here we show that mice deficient for S6K1 or S6K2 are born at the expected Mendelian ratio. Compared to wild-type mice, S6K1-/- mice are significantly smaller, whereas S6K2-/- mice tend to be slightly larger. However, mice lacking both genes showed a sharp reduction in viability due to perinatal lethality. Analysis of S6 phosphorylation in the cytoplasm and nucleoli of cells derived from the distinct S6K genotypes suggests that both kinases are required for full S6 phosphorylation but that S6K2 may be more prevalent in contributing to this response. Despite the impairment of S6 phosphorylation in cells from S6K1-/-/S6K2-/- mice, cell cycle progression and the translation of 5'-terminal oligopyrimidine mRNAs were still modulated by mitogens in a rapamycin-dependent manner. Thus, the absence of S6K1 and S6K2 profoundly impairs animal viability but does not seem to affect the proliferative responses of these cell types. Unexpectedly, in S6K1-/-/S6K2-/- cells, S6 phosphorylation persisted at serines 235 and 236, the first two sites phosphorylated in response to mitogens. In these cells, as well as in rapamycin-treated wild-type, S6K1-/-, and S6K2-/- cells, this step was catalyzed by a mitogen-activated protein kinase (MAPK)-dependent kinase, most likely p90rsk. These data reveal a redundancy between the S6K and the MAPK pathways in mediating early S6 phosphorylation in response to mitogens.

* Corresponding author. Mailing address for Mario Pende: INSERM 584, Hormone Targets, 156 Rue de Vaugirard, 75015 Paris, France. Phone: 0033 1 40 61 53 15. Fax: 0033 1 43 06 04 43. E-mail: pende{at}necker.fr. Mailing address for George Thomas: Friedrich Miescher Institute for Biomedical Research, Maulbeerstr. 66, 4058 Basel, Switzerland. Phone: 0041 61 697 3012. Fax: 0041 61 697 3976. E-mail: gthomas{at}fmi.ch.

Molecular and Cellular Biology, April 2004, p. 3112-3124, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3112-3124.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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