The LxCxE pRb interaction domain of cyclin D1 is dispensable for murine development.
Cyclin D1 is a multifunctional, tumor-associated protein that interacts with pRb via a conserved LxCxE motif, activates a kinase partner, directs the phosphorylation of pRb, activates cyclin E-cyclin-dependent kinase 2 (cdk2) by titrating Cip/Kip cdk inhibitors, and modulates the activity of a variety of transcription factors. It is thought that some of the proproliferative function of cyclin D1 is exerted by LxCxE-dependent binding to the pRb pocket domain, which might interfere with the ability of pRb to repress transcription by recruiting cellular chromatin remodeling proteins to E2F-dependent promoters. To test the importance of the LxCxE domain in vivo, we have generated a "knock-in" mouse by replacing the wild-type cyclin D1 gene with a mutant allele precisely lacking the nucleotides encoding the LxCxE domain. Analysis of this mouse has shown that the LxCxE protein is biochemically similar to wild-type cyclin D1 in all tested respects. Moreover, we were unable to detect abnormalities in growth, retinal development, mammary gland development, or tumorigenesis, all of which are affected by deleting cyclin D1. Although we cannot exclude the presence of subtle defects, these results suggest that the LxCxE domain of cyclin D1 is not necessary for function despite the absolute conservation of this motif in the D-type cyclins from plants and vertebrates.
Landis
Mark W
MW
Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA.
Brown
Nelson E
NE
Baker
Gregory L
GL
Shifrin
Anna
A
Das
Manjusri
M
Geng
Yan
Y
Sicinski
Piotr
P
Hinds
Philip W
PW
D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D019940:Genes, bcl-1; D008321:Mammary Glands, Animal / Q000254:growth & development*; D051379:Mice; D017434:Protein Structure, Tertiary; D012160:Retina / Q000254:growth & development* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1