The c-Jun NH2-terminal kinase 2 plays a dominant role in human epidermal neoplasia.
The c-Jun NH(2)-terminal kinase (JNK) signaling cascade has been implicated in a wide range of diseases, including cancer. It is unclear how different JNK proteins contribute to human cancer. Here, we report that JNK2 is activated in more than 70% of human squamous cell carcinoma (SCC) samples and that inhibition of JNK2 pharmacologically or genetically impairs tumorigenesis of human SCC cells. Most importantly, JNK2, but not JNK1, is sufficient to couple with oncogenic Ras to transform primary human epidermal cells into malignancy with features of SCC. JNK2 prevents Ras-induced cell senescence and growth arrest by reducing the expression levels of the cell cycle inhibitor p16 and the activation of NF-kappaB. On the other hand, JNK, along with phosphoinositide 3-kinase, is essential for Ras-induced glycolysis, an energy-producing process known to benefit cancer growth. These data indicate that JNK2 collaborates with other oncogenes, such as Ras, at multiple molecular levels to promote tumorigenesis and hence represents a promising therapeutic target for cancer.
Ke
Hengning
H
Department of Dermatology and Pharmacology, Duke University, Durham, North Carolina, USA.
Harris
Rebecca
R
Coloff
Jonathan L
JL
Jin
Jane Y
JY
Leshin
Benjamin
B
Miliani de Marval
Paula
P
Tao
Shiying
S
Rathmell
Jeffrey C
JC
Hall
Russell P
RP
Zhang
Jennifer Y
JY
D000818:Animals; D001706:Biopsy / Q000379:methods; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology*; D018631:ras Proteins / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D018076:DNA, Complementary; D048056:Mitogen-Activated Protein Kinase 9; D018631:ras Proteins