Absence of p21 partially rescues Mdm4 loss and uncovers an antiproliferative effect of Mdm4 on cell growth

Oncogene. 2004 Jan 8;23(1):303-6. doi: 10.1038/sj.onc.1206925.


Mdm4 (MdmX) is a p53-binding protein that shares structural similarities with Mdm2 and has been proposed to be a negative regulator of p53 function. Like Mdm2, the absence of Mdm4 has recently been found to induce embryonic lethality in mice that is rescued by p53 deletion. Mdm4-null embryos are reduced in size and die at mid-gestation, and Mdm4-deficient embryos and embryonic fibroblasts displayed reduced rates of cell proliferation. The p53-induced, cyclin-dependent kinase inhibitor p21 is strongly upregulated in Mdm4-null embryos and cells. Here, we report that deletion of p21 delays the mid-gestation lethality observed in Mdm4-null mice, suggesting that Mdm4 downregulates p53-mediated suppression of cell growth. Surprisingly, the absence of p21 also uncovers an antiproliferative effect of Mdm4 on cell growth in vitro and in Mdm4-heterozygous mice. These results indicate that p21 is a downstream modifier of Mdm4, and provides genetic evidence that Mdm4 can function to regulate cell growth both positively and negatively.

Publication types

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

MeSH terms

  • Animals
  • Cell Cycle Proteins*
  • Cell Division
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / physiology*
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • Embryo, Mammalian / cytology
  • Female
  • Fibroblasts / physiology
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins / physiology*
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / physiology
  • Ubiquitin-Protein Ligases


  • Cdkn1a protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Mdm4 protein, mouse
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases