title: S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy.
abstract: Rapamycin is an antibiotic inhibiting eukaryotic cell growth and proliferation by acting on target of rapamycin (TOR) kinase. Mammalian TOR (mTOR) is thought to work through 2 independent complexes to regulate cell size and cell replication, and these 2 complexes show differential sensitivity to rapamycin. Here we combine functional genetics and pharmacological treatments to analyze rapamycin-sensitive mTOR substrates that are involved in cell proliferation and tissue regeneration after partial hepatectomy in mice. After hepatectomy, hepatocytes proliferated rapidly, correlating with increased S6 kinase phosphorylation, while treatment with rapamycin derivatives impaired regeneration and blocked S6 kinase activation. In addition, genetic deletion of S6 kinase 1 (S6K1) caused a delay in S phase entry in hepatocytes after hepatectomy. The proliferative defect of S6K1-deficient hepatocytes was cell autonomous, as it was also observed in primary cultures and hepatic overexpression of S6K1-rescued proliferation. We found that S6K1 controlled steady-state levels of cyclin D1 (Ccnd1) mRNA in liver, and cyclin D1 expression was required to promote hepatocyte cell cycle. Notably, in vivo overexpression of cyclin D1 was sufficient to restore the proliferative capacity of S6K-null livers. The identification of an S6K1-dependent mechanism participating in cell proliferation in vivo may be relevant for cancer cells displaying high mTOR complex 1 activity and cyclin D1 accumulation.
authors.affiliation: Inserm, U845, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Espeillac
authors.forename: Claudia
authors.initials: C
authors.lastname: Mitchell
authors.forename: Séverine
authors.initials: S
authors.lastname: Celton-Morizur
authors.forename: Céline
authors.initials: C
authors.lastname: Chauvin
authors.forename: Vonda
authors.initials: V
authors.lastname: Koka
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gillet
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Albrecht
authors.forename: Chantal
authors.initials: C
authors.lastname: Desdouets
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D008115:Liver Regeneration / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D011506:Proteins / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D000903:Antibiotics, Antineoplastic; D007527:Isoenzymes; D046912:Multiprotein Complexes; D011506:Proteins; D019938:Cyclin D1; D000076222:Mechanistic Target of Rapamycin Complex 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus