The Drosophila mitochondrial ribosomal protein mRpL12 is required for Cyclin D/Cdk4-driven growth

EMBO J. 2005 Feb 9;24(3):623-34. doi: 10.1038/sj.emboj.7600523. Epub 2005 Feb 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division
  • Cyclin D
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism
  • Electron Transport Complex IV / biosynthesis
  • Eye / growth & development
  • Fat Body / growth & development
  • Genes, Insect
  • Homozygote
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Models, Biological
  • Mutation
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism*
  • Succinate Dehydrogenase / biosynthesis
  • Wings, Animal / growth & development

Substances

  • CycD protein, Drosophila
  • Cyclin D
  • Cyclins
  • Drosophila Proteins
  • Mitochondrial Proteins
  • Proto-Oncogene Proteins
  • Ribosomal Proteins
  • Hif prolyl hydroxylase, Drosophila
  • Procollagen-Proline Dioxygenase
  • Succinate Dehydrogenase
  • Electron Transport Complex IV
  • Cdk4 protein, Drosophila
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases