Heme controls the expression of cell cycle regulators and cell growth in HeLa cells

Biochem Biophys Res Commun. 2004 Mar 12;315(3):546-54. doi: 10.1016/j.bbrc.2004.01.092.


Heme plays a central role in oxygen utilization and in the generation of cellular energy. Here we examined the effect of heme and heme deficiency on cell cycle progression and the expression of key regulators in HeLa cells. We found that inhibition of heme synthesis causes cell cycle arrest and induces the expression of molecular markers associated with senescence and apoptosis, such as increased formation of PML nuclear bodies. Our data show that succinyl acetone-induced heme deficiency increases the protein levels of the tumor suppressor gene product p53 and CDK inhibitor p21, and decreases the protein levels of Cdk4, Cdc2, and cyclin D2. Further, we found that heme deficiency diminishes the activation/phosphorylation of Raf, MEK1/2, and ERK1/2-components of the MAP kinase signaling pathway. Our results show that heme is a versatile molecule that can effectively control cell growth and survival by acting on multiple regulators.

Publication types

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

MeSH terms

  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Cycle Proteins / biosynthesis*
  • Cell Division / drug effects
  • Cell Division / physiology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Gene Expression Regulation
  • HeLa Cells
  • Heme / antagonists & inhibitors
  • Heme / biosynthesis
  • Heme / deficiency
  • Heme / physiology*
  • Heptanoates / pharmacology
  • Humans
  • In Situ Nick-End Labeling
  • Matrix Metalloproteinase 3 / biosynthesis
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins*
  • Phosphorylation
  • Promyelocytic Leukemia Protein
  • Proto-Oncogene Proteins c-raf / metabolism
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Proteins


  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Heptanoates
  • Neoplasm Proteins
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • PML protein, human
  • Heme
  • succinylacetone
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Matrix Metalloproteinase 3