ATF-2 controls transcription of Maspin and GADD45 alpha genes independently from p53 to suppress mammary tumors.
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.
Maekawa
T
T
Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, Koyadai, Tsukuba, Ibaraki, Japan. maekawa@rtc.riken.jp
Sano
Y
Y
Shinagawa
T
T
Rahman
Z
Z
Sakuma
T
T
Nomura
S
S
Licht
J D
JD
Ishii
S
S
D051698:Activating Transcription Factor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D019313:BRCA1 Protein / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D015843:Serpins / Q000096:biosynthesis / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000097642:GADD45 Proteins
D051698:Activating Transcription Factor 2; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D015843:Serpins; D016159:Tumor Suppressor Protein p53; C497106:Atf2 protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C085344:SERPIN-B5