Disruption of cyclin D3 blocks proliferation of normal B-1a cells, but loss of cyclin D3 is compensated by cyclin D2 in cyclin D3-deficient mice.
Peritoneal B-1a cells differ from splenic B-2 cells in the molecular mechanisms that control G(0)-S progression. In contrast to B-2 cells, cyclin D2 is up-regulated in a rapid and transient manner in phorbol ester (PMA)-stimulated B-1a cells, whereas cyclin D3 does not accumulate until late G(1) phase. This nonoverlapping expression of cyclins D2 and D3 suggests distinct functions for these proteins in B-1a cells. To investigate the contribution of cyclin D3 in the proliferation of B-1a cells, we transduced p16(INK4a) peptidyl mimetics (TAT-p16) into B-1a cells before cyclin D3 induction to specifically block cyclin D3-cyclin-dependent kinase 4/6 assembly. TAT-p16 inhibited DNA synthesis in B-1a cells stimulated by PMA, CD40L, or LPS as well as endogenous pRb phosphorylation by cyclin D-cyclin-dependent kinase 4/6. Unexpectedly, however, cyclin D3-deficient B-1a cells proliferated in a manner similar to wild-type B-1a cells following PMA or LPS stimulation. This was due, at least in part, to the compensatory sustained accumulation of cyclin D2 throughout G(0)-S progression. Taken together, experiments in which cyclin D3 was inhibited in real time demonstrate the key role this cyclin plays in normal B-1a cell mitogenesis, whereas experiments with cyclin D3-deficient B-1a cells show that cyclin D2 can compensate for cyclin D3 loss in mutant mice.
Mataraza
Jennifer M
JM
Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
Tumang
Joseph R
JR
Gumina
Maria R
MR
Gurdak
Sean M
SM
Rothstein
Thomas L
TL
Chiles
Thomas C
TC
D000595:Amino Acid Sequence; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D056742:Cyclin D2; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000235:genetics; D018390:Gene Targeting; D006131:Growth Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010455:Peptides / Q000037:antagonists & inhibitors / Q000235:genetics; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D014161:Transduction, Genetic
C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D015696:Gene Products, tat; D006131:Growth Inhibitors; D010455:Peptides; D016160:Retinoblastoma Protein; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6