The signaling pathways that regulate cell growth are themselves subject
regulation, and there is great interest in identifying the factors that
control the activity of these pathways in vivo.
To investigate the regulation of the p53-Mdm2-Arf tumor suppressor pathway,
Inoue et al. studied mice deficient in Dmp1, a nuclear phosphoprotein that
transcriptionally activates the Arf gene. In their second year of life,
mice lacking one or both copies of the Dmp1 gene spontaneously developed
tumors in many different tissues. Dmp1 loss accelerated tumorigenesis in a
mouse lymphoma model, and the resultant tumors were notably devoid of
mutations in p53 and Arf, suggesting that Dmp1 is a potent modifier of the
p53-Mdm2-Arf pathway. It is possible that the minor subset of human tumors
that show no evidence of mutation in p53 or Arf may, in fact, have
mutations in the genes encoding key regulatory factors such as Dmp,
producing the same disruptive effect on cell growth control. -- PAK
Genes Dev., in press.