Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6.
Cdk4 and Cdk6 are thought to be essential for initiation of the cell cycle in response to mitogenic stimuli. Previous studies have shown that Cdk4 is dispensable for proliferation in most cell types, an observation attributed to a putative compensatory role by Cdk6. Cdk6-null mice are viable and develop normally although hematopoiesis is slightly impaired. Embryos defective for Cdk4 and Cdk6 die during the late stages of embryonic development due to severe anemia. However, these embryos display normal organogenesis and most cell types proliferate normally. In vitro, embryonic fibroblasts lacking Cdk4 and Cdk6 proliferate and become immortal upon serial passage. Moreover, quiescent Cdk4/Cdk6-null cells respond to serum stimulation and enter S phase with normal kinetics although with lower efficiency. These results indicate that D-type cyclin-dependent kinases are not essential for cell cycle entry and suggest the existence of alternative mechanisms to initiate cell proliferation upon mitogenic stimulation.
Malumbres
Marcos
M
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), E-28029 Madrid, Spain. malumbres@cnio.es
Sotillo
Rocío
R
Santamaría
David
D
Galán
Javier
J
Cerezo
Ana
A
Ortega
Sagrario
S
Dubus
Pierre
P
Barbacid
Mariano
M
D000818:Animals; D018929:Cell Culture Techniques; D002453:Cell Cycle; D002455:Cell Division; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000502:physiology*; D018076:DNA, Complementary / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005821:Genetic Techniques; D006412:Hematopoietic Stem Cells; D007150:Immunohistochemistry; D007700:Kinetics; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens; D008957:Models, Genetic; D011518:Proto-Oncogene Proteins; D016196:S Phase; D013997:Time Factors; D019076:Transgenes
D018076:DNA, Complementary; D008934:Mitogens; D011518:Proto-Oncogene Proteins; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases