TY - JOUR

T1 - Oncogenic Ras induces p19ARF and growth arrest in mouse embryo fibroblasts lacking p21Cip1 and p27Kip1 without activating cyclin D-dependent kinases.

AU - Groth, A

AU - Weber, J D

AU - Willumsen, Berthe Marie

AU - Sherr, C J

AU - Roussel, M F

N1 - Keywords: 3T3 Cells; Animals; Cell Cycle; Cell Cycle Proteins; Cell Division; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Cyclins; Embryo, Mammalian; Enzyme Activation; Fibroblasts; Humans; Mice; Microtubule-Associated Proteins; Oncogene Protein p21(ras); Protein Biosynthesis; Tumor Suppressor Protein p14ARF; Tumor Suppressor Proteins

PY - 2000

Y1 - 2000

N2 - Oncogenic Ras induces two products of the INK4a/ARF tumor suppressor locus (p16(INK4a) and p19(ARF)) in primary human and rodent fibroblasts, ultimately leading to a permanent state of cell cycle arrest resembling replicative senescence. Whereas p16(INK4a) antagonizes the activities of cyclin D-dependent kinases, p19(ARF) activates the p53 transcription factor. Immortalized rodent fibroblast cell lines that lack INK4a/ARF function, ARF alone, or p53 are resistant to the growth inhibitory effects of oncogenic Ras and instead continue to proliferate and undergo morphological transformation. Primary mouse embryo fibroblasts lacking Cip1 and Kip1 genes encoding inhibitors of cyclin-dependent kinase-2 were used to further explore the effects of oncogenic Ras on arrest of the cell division cycle. Although early passage primary fibroblast strains that lack both p21(Cip1) and p27(Kip1) fail to assemble cyclin D-dependent kinases, oncogenic Ras retained its ability to induce p19(ARF), but not p16(INK4a), protecting Cip/Kip-null cells from proliferating and undergoing transformation. Under these conditions, Ras did not induce G(1) phase arrest but instead triggered DNA synthesis, abnormal nuclear divisions, failure of cytokinesis, and emergence of polyploid cells. Therefore, in the absence of p16(INK4a), p21(Cip1), and p27(Kip1), oncogenic Ras affects the functions of genes required for completion of the cell cycle.

AB - Oncogenic Ras induces two products of the INK4a/ARF tumor suppressor locus (p16(INK4a) and p19(ARF)) in primary human and rodent fibroblasts, ultimately leading to a permanent state of cell cycle arrest resembling replicative senescence. Whereas p16(INK4a) antagonizes the activities of cyclin D-dependent kinases, p19(ARF) activates the p53 transcription factor. Immortalized rodent fibroblast cell lines that lack INK4a/ARF function, ARF alone, or p53 are resistant to the growth inhibitory effects of oncogenic Ras and instead continue to proliferate and undergo morphological transformation. Primary mouse embryo fibroblasts lacking Cip1 and Kip1 genes encoding inhibitors of cyclin-dependent kinase-2 were used to further explore the effects of oncogenic Ras on arrest of the cell division cycle. Although early passage primary fibroblast strains that lack both p21(Cip1) and p27(Kip1) fail to assemble cyclin D-dependent kinases, oncogenic Ras retained its ability to induce p19(ARF), but not p16(INK4a), protecting Cip/Kip-null cells from proliferating and undergoing transformation. Under these conditions, Ras did not induce G(1) phase arrest but instead triggered DNA synthesis, abnormal nuclear divisions, failure of cytokinesis, and emergence of polyploid cells. Therefore, in the absence of p16(INK4a), p21(Cip1), and p27(Kip1), oncogenic Ras affects the functions of genes required for completion of the cell cycle.

U2 - 10.1074/jbc.M003417200

DO - 10.1074/jbc.M003417200

M3 - Journal article

C2 - 10842176

VL - 275

SP - 27473

EP - 27480

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 35

ER -