Critical requirement for cell cycle inhibitors in sustaining nonproliferative states.
In adult vertebrates, most cells are not in the cell cycle at any one time. Physiological nonproliferation states encompass reversible quiescence and permanent postmitotic conditions such as terminal differentiation and replicative senescence. Although these states appear to be attained and maintained quite differently, they might share a core proliferation-restricting mechanism. Unexpectedly, we found that all sorts of nonproliferating cells can be mitotically reactivated by the sole suppression of histotype-specific cyclin-dependent kinase (cdk) inhibitors (CKIs) in the absence of exogenous mitogens. RNA interference-mediated suppression of appropriate CKIs efficiently triggered DNA synthesis and mitosis in established and primary terminally differentiated skeletal muscle cells (myotubes), quiescent human fibroblasts, and senescent human embryo kidney cells. In serum-starved fibroblasts and myotubes alike, cell cycle reactivation was critically mediated by the derepression of cyclin D-cdk4/6 complexes. Thus, both temporary and permanent growth arrest must be actively maintained by the constant expression of CKIs, whereas the cell cycle-driving cyclins are always present or can be readily elicited. In principle, our findings could find wide application in biotechnology and tissue repair whenever cell proliferation is limiting.
Pajalunga
Deborah
D
Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Roma, Italy.
Mazzola
Alessia
A
Salzano
Anna Maria
AM
Biferi
Maria Grazia
MG
De Luca
Gabriele
G
Crescenzi
Marco
M
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D016213:Cyclins / Q000378:metabolism; D004261:DNA Replication / Q000502:physiology; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D034622:RNA Interference
C534696:CCND3 protein, human; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6