Activated Src abrogates the Myc requirement for the G0/G1 transition but not for the G1/S transition.
The transcription factor Myc plays a central role in the control of cellular proliferation. Myc expression is induced by growth factors in a pathway mediated by cellular Src (c-Src), but it is not clear whether Myc induction or activity is required for malignant transformation by activated Src. We introduced v-Src into a c-myc(-/-) derivative of Rat-1 fibroblasts and into 3T9 mouse fibroblasts harboring a conditionally excisable c-myc allele. Expression of activated viral Src in Myc-deficient cells led to loss of actin stress fibers and surface fibronectin, indicating that Myc is dispensable for v-Src-induced morphological transformation. However, v-Src failed to rescue the proliferative defect resulting from the loss of Myc. In Myc-deficient cells, despite its inability to overcome this proliferation block, v-Src was able to regulate the expression of certain Myc transcriptional targets and induce the expression of active cyclin D/Cdk4 and Cdk6 complexes; it also induced the phosphorylation of Rb, albeit at reduced levels. In contrast, however, in the absence of Myc, the level of Cdk2 kinase activity was drastically reduced. This reduction in Cdk2 activity was associated with a decrease in the expression of Cdk7, Cdc25A, and cyclin A. Coexpression of Cdk2 plus cyclin E and/or cyclin A rescued the G1/S block and allowed the cells to enter mitosis. These results indicate that in the absence of Myc, v-Src can activate early G1 cell cycle regulators but fails to activate regulators of the late G1/S transition.
Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720-3204, USA.
Tulsiram
T
Prathapam
Sarah
S
Tegen
Thordur
T
Oskarsson
Andreas
A
Trumpp
G Steven
GS
Martin
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase; D007399:Interphase / Q000235:genetics*; D051379:Mice; D009154:Mutation; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D051381:Rats; D016192:Resting Phase, Cell Cycle; D016196:S Phase; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D015688:Oncogene Protein pp60(v-src); D018844:Cyclin-Dependent Kinases