title: The Drosophila mitochondrial ribosomal protein mRpL12 is required for Cyclin D/Cdk4-driven growth.
abstract: The Drosophila melanogaster cyclin-dependent protein kinase complex CycD/Cdk4 stimulates both cell cycle progression and cell growth (accumulation of mass). CycD/Cdk4 promotes cell cycle progression via the well-characterized RBF/E2F pathway, but our understanding of how growth is stimulated is still limited. To identify growth regulatory targets of CycD/Cdk4, we performed a loss-of-function screen for modifiers of CycD/Cdk4-induced overgrowth of the Drosophila eye. One mutation that suppressed CycD/Cdk4 was in a gene encoding the mitochondrial ribosomal protein, mRpL12. We show here that mRpL12 is required for CycD/Cdk4-induced cell growth. Cells homozygous mutant for mRpL12 have reduced mitochondrial activity, and exhibit growth defects that are very similar to those of cdk4 null cells. CycD/Cdk4 stimulates mitochondrial activity, and this is mRpL12 dependent. Hif-1 prolyl hydroxylase (Hph), another effector of CycD/Cdk4, regulates growth and is required for inhibition of the hypoxia-inducible transcription factor 1 (Hif-1). Both functions depend on mRpL12 dosage, suggesting that CycD/Cdk4, mRpL12 and Hph function together in a common pathway that controls cell growth via affecting mitochondrial activity.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. christian.frei@zool.unizh.ch
authors.forename: Christian
authors.initials: C
authors.lastname: Frei
authors.forename: Mireille
authors.initials: M
authors.lastname: Galloni
authors.forename: Ernst
authors.initials: E
authors.lastname: Hafen
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Edgar
mesh_terms: D000818:Animals; D002455:Cell Division; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000096:biosynthesis; D005123:Eye / Q000254:growth & development; D005216:Fat Body / Q000254:growth & development; D017344:Genes, Insect; D006720:Homozygote; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000096:biosynthesis; D014921:Wings, Animal / Q000254:growth & development
chemical_list: C534694:CycD protein, Drosophila; D056741:Cyclin D; D016213:Cyclins; D029721:Drosophila Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D012269:Ribosomal Proteins; C491512:Hif prolyl hydroxylase, Drosophila; D011393:Procollagen-Proline Dioxygenase; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; C495896:Cdk4 protein, Drosophila; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases