S100P stimulates cell proliferation and survival via receptor for activated glycation end products (RAGE).
S100P is a member of the S100 protein family that is expressed in several malignant neoplasms. Currently the effects of this molecule on cell function are unknown. In the present study we investigated the biological effects and mechanisms of action of S100P using NIH3T3 cells. Expression of S100P in NIH3T3 cells led to the presence of S100P in the culture medium, increased cellular proliferation, and enhanced survival after detachment from the culture substrate or after exposure to the chemotherapeutic agent 5-flurouracil. The proliferation and survival effects of S100P expression were duplicated in a time- and concentration-dependent manner by the extracellular addition of purified S100P to wild-type NIH3T3 cells and correlated with the activation of extracellular-regulated kinases (Erks) and NF-kappaB. To determine the mechanisms involved in these effects, we tested the hypothesis that S100P activated RAGE (receptor for activated glycation end products). We found that S100P co-immunoprecipitated with RAGE. Furthermore, the effects of S100P on cell signaling, proliferation, and survival were blocked by agents that interfere with RAGE including administration of an amphoterin-derived peptide known to antagonize RAGE activation, anti-RAGE antibodies, and by expression of a dominant negative RAGE. These data suggest that S100P can act in an autocrine manner via RAGE to stimulate cell proliferation and survival.
Arumugam
Thiruvengadam
T
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Simeone
Diane M
DM
Schmidt
Ann Marie
AM
Logsdon
Craig D
CD
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002455:Cell Division; D002469:Cell Separation; D002470:Cell Survival; D003470:Culture Media / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D002135:Calcium-Binding Proteins; D003470:Culture Media; D018076:DNA, Complementary; D016328:NF-kappa B; D009363:Neoplasm Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C103003:S100P protein, human; D020928:Mitogen-Activated Protein Kinases; D005472:Fluorouracil