Molecular markers of IGF-I-mediated mitogenesis.
The aim of these investigations was to identify a number of molecular markers that correlate to growth stimulation by IGF-I. For this purpose, we have selected four cell lines that respond equally well to growth stimulation by serum, but differ in their proliferative response to IGF-I. Two cell lines (R503 and R600 cells) respond to IGF-I with both DNA synthesis and cell division, a third cell line (R508 cells) can enter S phase after IGF-I, but the cells do not divide, and a fourth one (R12 cells) totally fails to respond to IGF-I with growth. Using these cell lines, all of which had an intact mitogenic response program to serum, we show that: (1) an increase in GTP/GDP ratio is an early event that distinguishes cells capable of entering S phase after IGF-I from cells that do not; (2) all cells that are induced to synthesize DNA by IGF-I have increased phosphorylation of MAP kinases, regardless of their ability to divide; (3) the same cell lines display a similar increase in cyclin A and B expression at early times after stimulation; and (4) cyclin levels and cyclin B-associated cdc2 kinase activity remain elevated at later times only in cells that undergo cell division. These results establish certain parameters of IGF-I-mediated mitogenesis and clearly separate the occurrence of DNA synthesis from cell division in certain situations.
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
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D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis*; D001769:Blood; D016203:CDC2 Protein Kinase / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D019925:Cyclin A / Q000096:biosynthesis; D019926:Cyclin B / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D006153:Guanosine Diphosphate / Q000032:analysis; D006160:Guanosine Triphosphate / Q000032:analysis; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D016196:S Phase
D015415:Biomarkers; D019925:Cyclin A; D019926:Cyclin B; D008934:Mitogens; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D006153:Guanosine Diphosphate; D007334:Insulin-Like Growth Factor I; D006160:Guanosine Triphosphate; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016203:CDC2 Protein Kinase; D016283:Proto-Oncogene Proteins p21(ras)