Synergy between the Mos/mitogen-activated protein kinase pathway and loss of p53 function in transformation and chromosome instability.
Constitutive activation of mitogen-activated protein kinase (MAPK) is a property common to many oncoproteins, including Mos, Ras, and Raf, and is essential for their transforming activities. We have shown that high levels of expression of the Mos/MAPK pathway in Swiss 3T3 fibroblast cause cells in S phase to undergo apoptosis, while cells in G1 irreversibly growth arrest. Interestingly, cells in G2 and M phases also arrest at a G1-like checkpoint after proceeding through mitosis. These cells fail to undergo cytokinesis and are binucleated. Thus, constitutive overexpression of Mos and MAPK cannot be tolerated, and fibroblasts transformed by Mos express only low levels of the mos oncogene product. Here, we show that p53 plays a key role in preventing oncogene-mediated activation of MAPK. In the absence of p53 (p53-/-), the growth arrest normally observed in wild-type p53 (p53+/+) mouse embryo fibroblasts (MEFs) is markedly reduced. The mos transformation efficiency in p53-/- MEFs is two to three orders of magnitude higher than that in p53+/+ cells, and p53-/- cells tolerate > 10-fold higher levels of both Mos and activated MAPK. Moreover, we show that, like Mos, both v-ras and v-raf oncogene products induce apoptosis in p53+/+ MEFs. These oncogenes also display a high transforming activity in p53-/- MEFs, as does a gain-of-function MAPK kinase mutant (MEK*). Thus, the p53-dependent checkpoint pathway is responsive to oncogene-mediated MAPK activation in inducing irreversible G1 growth arrest and apoptosis. Moreover, we show that the chromosome instability induced by the loss of p53 is greatly enhanced by the constitutive activation of the Mos/MAPK pathway.
Fukasawa
K
K
ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Vande Woude
G F
GF
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002875:Chromosomes / Q000235:genetics*; D004789:Enzyme Activation; D005347:Fibroblasts; D015870:Gene Expression; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics; D008980:Moloney murine sarcoma virus / Q000235:genetics; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000502:physiology; D027384:Oncogene Proteins v-raf; D009857:Oncogenes; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D017231:Proto-Oncogene Proteins c-mos / Q000502:physiology*; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D015682:Retroviridae Proteins, Oncogenic; D016159:Tumor Suppressor Protein p53; D027384:Oncogene Proteins v-raf; D017346:Protein Serine-Threonine Kinases; D017231:Proto-Oncogene Proteins c-mos; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D015689:Oncogene Protein p21(ras)