Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo.
Cyclin D1 is part of a cell cycle control node consistently deregulated in most human cancers. However, studies with cyclin D1-null mice indicate that it is dispensable for normal mouse development as well as cell growth in culture. Here, we provide evidence that ras-mediated tumorigenesis depends on signaling pathways that act preferentially through cyclin D1. Cyclin D1 expression and the activity of its associated kinase are up-regulated in keratinocytes in response to oncogenic ras. Furthermore, cyclin D1 deficiency results in up to an 80% decrease in the development of squamous tumors generated through either grafting of retroviral ras-transduced keratinocytes, phorbol ester treatment of ras transgenic mice, or two-stage carcinogenesis.
The University of Texas, M.D. Anderson Cancer Center, Science Park-Research Division (SPRD), Smithville, Texas 78957 USA.
A I
AI
Robles
M L
ML
Rodriguez-Puebla
A B
AB
Glick
C
C
Trempus
L
L
Hansen
P
P
Sicinski
R W
RW
Tennant
R A
RA
Weinberg
S H
SH
Yuspa
C J
CJ
Conti
D000818:Animals; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019927:Cyclin E / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins; D012190:Retroviridae / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000503:physiopathology*
D019927:Cyclin E; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases