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Molecular and Cellular Biology, January 2005, p. 220-232, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.220-232.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Ras-Raf-Arf Signaling Critically Depends on the Dmp1 Transcription Factor

Ramesh Sreeramaneni,1,{dagger} Asif Chaudhry,1,{dagger} Martin McMahon,2 Charles J. Sherr,3 and Kazushi Inoue1*

Departments of Pathology and Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina,1 Cancer Research Institute and Department of Cellular and Molecular Pharmacology, UCSF/Mt. Zion Comprehensive Cancer Center, San Francisco, California,2 Howard Hughes Medical Institute, Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee3

Received 6 July 2004/ Returned for modification 3 September 2004/ Accepted 8 October 2004

Dmp1 prevents tumor formation by activating the Arf-p53 pathway. In cultured primary cells, the Dmp1 promoter was efficiently activated by oncogenic Ha-RasV12, but not by overexpressed c-Myc or E2F-1. Dmp1 promoter activation by RasV12 depended on Raf-MEK-ERK signaling. Induction of p19Arf and p21Cip1 by oncogenic Raf was compromised in Dmp1-null cells, which were resistant to Raf-mediated premature senescence. A RasV12-responsive element was mapped to the 5' leader sequence of the murine Dmp1 promoter, where endogenous Fos and Jun family proteins bind. Dmp1 promoter activation by RasV12 was strikingly impaired in c-Jun as well as in JunB knock-down cells, suggesting the critical role of Jun proteins in the activation of the Dmp1 promoter. A RasV12-responsive element was mapped to the unique Dmp1/Ets site on the Arf promoter, where endogenous Dmp1 proteins bind upon oncogenic Raf activation. Therefore, activation of Arf by Ras/Raf signaling is indirectly mediated by Dmp1, explaining why Dmp1-null primary cells are highly susceptible to Ras-induced transformation. Our data indicate the presence of the novel Jun-Dmp1 pathway that directly links oncogenic Ras-Raf signaling and p19Arf, independent of the classical cyclin D1/Cdk4-Rb-E2F pathway.

* Corresponding author. Mailing address: Department of Pathology, Wake Forest University Health Sciences, 2102 Gray Building, Medical Center Blvd., Winston-Salem, NC 27157. Phone: (336) 716-5863. Fax: (336) 716-6757. E-mail: kinoue{at}wfubmc.edu.

{dagger} R.S. and A.C. contributed equally to this work.

Molecular and Cellular Biology, January 2005, p. 220-232, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.220-232.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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