Drosophila cyclin D/Cdk4 requires Hif-1 prolyl hydroxylase to drive cell growth

Dev Cell. 2004 Feb;6(2):241-51. doi: 10.1016/s1534-5807(03)00409-x.

Abstract

The Drosophila cyclin-dependent protein kinase complex Cyclin D/Cdk4 induces cell growth (accumulation of mass) as well as proliferation (cell cycle progression). To understand how CycD/Cdk4 promotes growth, we performed a screen for modifiers of CycD/Cdk4-driven overgrowth in the eye. Loss-of-function mutations in Hif-1 prolyl hydroxylase (Hph), an enzyme involved in the cellular response to hypoxic stress, dominantly suppress the growth but not the proliferation function of CycD/Cdk4. hph mutant cells are defective for growth, and, remarkably, ectopic expression of Hph is sufficient to increase cellular growth. Epistasis analysis places Hph downstream of CycD/Cdk4. Overexpressed CycD/Cdk4 causes an increase in Hph protein in tissues where Hph induces growth, suggesting a mechanism whereby Hph levels are regulated posttranscriptionally in response to CycD/Cdk4. Our data suggest that Hph, in addition to its function in hypoxic response, is a regulator of cellular growth and that it is a key mediator for CycD/Cdk4.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Blotting, Northern / methods
  • Body Weight / genetics
  • Cell Cycle
  • Cell Differentiation
  • Cell Division / physiology*
  • Cyclin D
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases / physiology*
  • Cyclins / physiology*
  • Drosophila / enzymology
  • Drosophila / growth & development*
  • Drosophila Proteins
  • Epistasis, Genetic
  • Eye / metabolism
  • Fat Body / metabolism
  • Gene Expression Regulation, Developmental
  • Green Fluorescent Proteins
  • Immunohistochemistry
  • Indoles / metabolism
  • Larva
  • Luminescent Proteins / metabolism
  • Microscopy, Electron, Scanning / methods
  • Models, Biological
  • Mutation
  • Procollagen-Proline Dioxygenase / physiology*
  • Proto-Oncogene Proteins*
  • RNA, Messenger / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction / methods

Substances

  • CycD protein, Drosophila
  • Cyclin D
  • Cyclins
  • Drosophila Proteins
  • Indoles
  • Luminescent Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Green Fluorescent Proteins
  • DAPI
  • Procollagen-Proline Dioxygenase
  • Cdk4 protein, Drosophila
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases