Disruption of c-Jun reduces cellular migration and invasion through inhibition of c-Src and hyperactivation of ROCK II kinase.
The spread of metastatic tumors to different organs is associated with poor prognosis. The metastatic process requires migration and cellular invasion. The protooncogene c-jun encodes the founding member of the activator protein-1 family and is required for cellular proliferation and DNA synthesis in response to oncogenic signals and plays an essential role in chemical carcinogenesis. The role of c-Jun in cellular invasion remains to be defined. Genetic deletion of c-Jun in transgenic mice is embryonic lethal; therefore, transgenic mice encoding a c-Jun gene flanked by LoxP sites (c-jun(f/f)) were used. c-jun gene deletion reduced c-Src expression, hyperactivated ROCK II signaling, and reduced cellular polarity, migration, and invasiveness. c-Jun increased c-Src mRNA abundance and c-Src promoter activity involving an AP-1 site in the c-Src promoter. Transduction of c-jun(-/-) cells with either c-Jun or c-Src retroviral expression systems restored the defective cellular migration of c-jun(-/-) cells. As c-Src is a critical component of pathways regulating proliferation, survival, and metastasis, the induction of c-Src abundance, by c-Jun, provides a novel mechanism of cooperative signaling in cellular invasion.
Jiao
Xuanmao
X
Department of Cancer Biology and Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Katiyar
Sanjay
S
Liu
Manran
M
Mueller
Susette C
SC
Lisanti
Michael P
MP
Li
Anping
A
Pestell
Timothy G
TG
Wu
Kongming
K
Ju
Xiaoming
X
Li
Zhiping
Z
Wagner
Erwin F
EF
Takeya
Tatsuo
T
Wang
Chenguang
C
Pestell
Richard G
RG
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000235:genetics* / Q000502:physiology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D022001:Focal Adhesions / Q000235:genetics / Q000502:physiology; D017353:Gene Deletion; D016758:Genes, jun; D016391:Genes, src; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D051419:Paxillin / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000199:Actins; D051419:Paxillin; C496062:Pxn protein, mouse; D012333:RNA, Messenger; D054460:rho-Associated Kinases