Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia.
The tumor necrosis factor alpha receptor (TNFR1) activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH(2)-kinase (JNK)/activator protein 1 (AP1) cascade. Here, we report that JNK is activated in a majority of spontaneous human squamous cell carcinomas (SCC). JNK pathway induction bypassed cell cycle restraints induced by oncogenic Ras and cooperated with Ras to convert normal human epidermis into tumors indistinguishable from SCC, confirming its oncogenic potency in human tissue. Inhibiting MKK7, JNK, and AP1 as well as TNFR1 itself using genetic, pharmacologic, or antibody-mediated approaches abolished invasive human epidermal neoplasia in a tumor cell autonomous fashion. The TNFR1/MKK7/JNK/AP1 cascade thus promotes human neoplasia and represents a potential therapeutic target for human epithelial cancers.
Zhang
Jennifer Y
JY
Department of Medicine, Division of Dermatology, Duke University School of Medicine, Trent Drive, Durham, NC 27710, USA. Jennifer.zhang@duke.edu
Adams
Amy E
AE
Ridky
Todd W
TW
Tao
Shiying
S
Khavari
Paul A
PA
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048688:MAP Kinase Kinase 7 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D047888:Receptors, Tumor Necrosis Factor, Type I; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; D018631:ras Proteins