The oncogene PDGF-B provides a key switch from cell death to survival induced by TNF.
Tumor necrosis factor (TNF) induces both cell death and survival signals. NF-kappaB, a transcription factor activated by TNF, is critical for controlling survival signals through trans-activation of downstream target genes. However, few NF-kappaB target survival genes have been identified with direct roles in oncogenesis. We report that platelet-derived growth factor B (PDGF-B), an oncogene and growth factor, is highly induced by TNF in fibroblasts in an NF-kappaB-dependent manner. PDGF-B can rescue NF-kappaB-deficient fibroblasts from TNF-mediated killing, and inhibition of PDGF-B signaling sensitizes wild-type cells to TNF-induced death. Interestingly, PDGF-B-transformed NIH-3T3 cells are even more highly sensitized to TNF-induced cell death with PDGF-B inhibition. Our results suggest that while normal cells contain multiple TNF-induced survival signals, tumor cells may favor a specific survival gene that is abnormally upregulated in order to evade death signals.
Au
P Y Billie
PY
AMDI/cFIFBCR, University Health Network, Department of Medical Biophysics, University of Toronto, 620 University Ave. Suite 7-706, Toronto, Ontario, Canada M5G 2C1.
Martin
Nicole
N
Chau
Hien
H
Moemeni
Behrouz
B
Chia
Marie
M
Liu
Fei-Fei
FF
Minden
Mark
M
Yeh
Wen-Chen
WC
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002461:Cell Line, Transformed; D002469:Cell Separation; D002470:Cell Survival; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D051550:I-kappa B Kinase; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
D016895:Culture Media, Serum-Free; D016328:NF-kappa B; D020574:Proto-Oncogene Proteins c-sis; D014409:Tumor Necrosis Factor-alpha; D017479:Receptors, Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases