FoxM1 regulates transcription of JNK1 to promote the G1/S transition and tumor cell invasiveness.
The Forkhead box M1 (FoxM1) protein is a proliferation-specific transcription factor that plays a key role in controlling both the G(1)/S and G(2)/M transitions through the cell cycle and is essential for the development of various cancers. We show here that FoxM1 directly activates the transcription of the c-Jun N-terminal kinase (JNK1) gene in U2OS osteosarcoma cells. Expression of JNK1, which regulates the expression of genes important for the G(1)/S transition, rescues the G(1)/S but not the G(2)/M cell cycle block in FoxM1-deficient cells. Knockdown of either FoxM1 or JNK1 inhibits tumor cell migration, invasion, and anchorage-independent growth. However, expression of JNK1 in FoxM1-depleted cells does not rescue these defects, indicating that JNK1 is a necessary but insufficient downstream mediator of FoxM1 in these processes. Consistent with this interpretation, FoxM1 regulates the expression of the matrix metalloproteinases MMP-2 and MMP-9, which play a role in tumor cell invasion, through JNK1-independent and -dependent mechanisms in U2OS cells, respectively. Taken together, these findings identify JNK1 as a critical transcriptional target of FoxM1 that contributes to FoxM1-regulated cell cycle progression, tumor cell migration, invasiveness, and anchorage-independent growth.
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, 900 S. Ashland Avenue, Chicago, IL 60607, USA.
I-Ching
IC
Wang
Yi-Ju
YJ
Chen
Douglas E
DE
Hughes
Timothy
T
Ackerson
Michael L
ML
Major
Vladimir V
VV
Kalinichenko
Robert H
RH
Costa
Pradip
P
Raychaudhuri
Angela L
AL
Tyner
Lester F
LF
Lau
D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D014158:Transcription, Genetic; D014162:Transfection
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D048055:Mitogen-Activated Protein Kinase 8; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9