Stress-induced secretion of growth inhibitors: a novel tumor suppressor function of p53.
p53 tumor suppressor gene controls cell response to a variety of stresses inducing growth arrest or apoptosis in damaged cells. It largely determines the sensitivity of tumor and normal cells to radiation and chemotherapy, and, therefore, defines both the efficacy and limitations of anti-cancer treatment. To determine molecular mechanisms of p53-dependent stress response in normal tissues we identified and compared the spectra of radiation-responsive genes in cells of different origin and p53 status using a cDNA array hybridization technique. The majority of genes identified were p53-dependent and cell type specific. Several of the new p53 responders encode known secreted growth inhibitory factors. This suggests that p53, in addition to its intrinsic antiproliferation activity, can cause 'bystander effect' by inducing export of growth suppressive stimuli from damaged cells to neighboring cells. Consistently, a p53-dependent accumulation of factors, which causes growth inhibitory effects in a variety of cell lines, was found after gamma irradiation in the media from established and primary cell cultures and in the urine of irradiated mice. Moreover, p53-dependent factors released by normal human fibroblasts potentiated the cytotoxic effect of a chemotherapeutic drug on co-cultivated tumor cells. This suggests a previously unknown role for normal cells in chemo- and radiation therapy of cancer.
Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, 60607, USA.
E A
EA
Komarova
L
L
Diatchenko
O W
OW
Rokhlin
J E
JE
Hill
Z J
ZJ
Wang
V I
VI
Krivokrysenko
E
E
Feinstein
A V
AV
Gudkov
D016475:3T3 Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D005720:Gamma Rays; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D005796:Genes / Q000235:genetics / Q000528:radiation effects; D016147:Genes, Tumor Suppressor / Q000235:genetics; D006131:Growth Inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013312:Stress, Physiological / Q000503:physiopathology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D016159:Tumor Suppressor Protein p53