Absence of p21 partially rescues Mdm4 loss and uncovers an antiproliferative effect of Mdm4 on cell growth.
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.
Steinman
Heather A
HA
Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Sluss
Hayla K
HK
Sands
Arthur T
AT
Pihan
German
G
Jones
Stephen N
SN
D000818:Animals; D018797:Cell Cycle Proteins; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D044767:Ubiquitin-Protein Ligases
C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases