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Molecular and Cellular Biology, February 2007, p. 1356-1369, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01061-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Somatic Excision Demonstrates that c-Jun Induces Cellular Migration and Invasion through Induction of Stem Cell Factor{triangledown} ,{dagger}

Sanjay Katiyar,1 Xuanmao Jiao,1 Erwin Wagner,2 Michael P. Lisanti,1 and Richard G. Pestell1*

Kimmel Cancer Center, Departments of Cancer Biology and Medical Oncology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, Pennsylvania 19107,1 Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, Vienna A-1030, Austria2

Received 13 June 2006/ Returned for modification 14 July 2006/ Accepted 18 November 2006

Cancer cells arise through sequential acquisition of mutations in tumor suppressors and oncogenes. c-Jun, a critical component of the AP-1 complex, is frequently overexpressed in diverse tumor types and has been implicated in promoting cellular proliferation, migration, and angiogenesis. Functional analysis of candidate genetic targets using germ line deletion in murine models can be compromised through compensatory mechanisms. As germ line deletion of c-jun induces embryonic lethality, somatic deletion of the c-jun gene was conducted using floxed c-jun (c-junf/f) conditional knockout mice. c-jun-deleted cells showed increased cellular adhesion, stress fiber formation, and reduced cellular migration. The reduced migratory velocity and migratory directionality was rescued by either c-Jun reintroduction or addition of secreted factors from wild-type cells. An unbiased analysis of cytokines and growth factors, differentially expressed and showing loss of secretion upon c-jun deletion, identified stem cell factor (SCF) as a c-Jun target gene. Immunoneutralizing antibody to SCF reduced migration of wild-type cells. SCF addition rescued the defect in cellular adhesion, cellular velocity, directional migration, transwell migration, and cellular invasion of c-jun–/– cells. c-Jun induced SCF protein, mRNA, and promoter activity. Induction of the SCF promoter required the c-Jun DNA-binding domain. c-Jun bound to the SCF promoter in chromatin immunoprecipitation assays. Mutation of the c-Jun binding site abolished c-Jun-mediated induction of the SCF promoter. These studies demonstrate an essential role of c-Jun in cellular migration through induction of SCF.

* Corresponding author. Mailing address: The Kimmel Cancer Center, Departments of Cancer Biology and Medical Oncology, Thomas Jefferson University, 233 South 10th St., Philadelphia, PA 19107. Phone: (215) 503-5649. Fax: (215) 503-9334. E-mail: Richard.Pestell{at}jefferson.edu.

{triangledown} Published ahead of print on 4 December 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2007, p. 1356-1369, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01061-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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