ATF-2 controls transcription of Maspin and GADD45 alpha genes independently from p53 to suppress mammary tumors

Oncogene. 2008 Feb 14;27(8):1045-54. doi: 10.1038/sj.onc.1210727. Epub 2007 Aug 13.


The activating transcription factor, ATF-2, is a target of p38 and JNK that are involved in stress-induced apoptosis. Heterozygous Atf-2 mutant (Atf-2+/-) mice are highly prone to mammary tumors. The apoptosis-regulated gene GADD45alpha and the breast cancer suppressor gene Maspin, both of which are known to be p53 target genes, are downregulated in the mammary tumors arisen in Atf-2+/- mice. Here, we have analysed how ATF-2 controls the transcription of GADD45alpha and Maspin. ATF-2 and p53 independently activate the GADD45alpha transcription. ATF-2 does not directly bind to the GADD45alpha promoter; instead, it is recruited via Oct-1 and NF-I. ATF-2 simultaneously binds to Oct-1, NF-I and breast cancer suppressor BRCA1 to activate transcription. With regard to Maspin, ATF-2 and p53 directly bind to different sites in the Maspin promoter to independently activate its transcription. Consistent with the observation that ATF-2 and p53 independently activate the transcription of Maspin and GADD45alpha is that the loss of one copy of p53 shortened the period required for mammary tumor development in Atf-2+/- mice. These studies suggest the functional link between the ATF-2 and the two tumor suppressors BRCA1 and p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2 / deficiency
  • Activating Transcription Factor 2 / genetics
  • Activating Transcription Factor 2 / physiology*
  • Animals
  • BRCA1 Protein / physiology
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics*
  • Cell Line
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / physiology*
  • Genes, Tumor Suppressor / physiology
  • Humans
  • Male
  • Mammary Neoplasms, Experimental / enzymology
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Mice, Mutant Strains
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics*
  • Serpins / biosynthesis
  • Serpins / genetics*
  • Tumor Suppressor Protein p53 / physiology*


  • Activating Transcription Factor 2
  • Atf2 protein, mouse
  • BRCA1 Protein
  • Cell Cycle Proteins
  • Gadd45a protein, mouse
  • Nuclear Proteins
  • Serpins
  • Tumor Suppressor Protein p53