Cyclin D1 and cyclin D3 show divergent responses to distinct mitogenic stimulation.
D-type cyclins predominantly regulate progression through the cell cycle by their interactions with cyclin-dependent kinases (cdks). Here, we show that stimulating mitogenesis of Swiss 3T3 cells with phorbol esters or forskolin can induce divergent responses in the expression levels, localization and activation state of cyclin D1 and cyclin D3. Phorbol ester-mediated protein kinase C stimulation induces S phase entry which is dependent on MAPK activation and increases the levels and activation of cyclin D1, whereas forskolin-mediated cAMP-dependent protein kinase A stimulation induces mitogenesis that is independent of MAPK, but dependent upon mTor and specifically increases the level and activation of cyclin D3. These findings uncover additional levels of complexity in the regulation of the cell cycle at the level of the D-type cyclins and thus may have important therapeutic implications in cancers where specific D-cyclins are overexpressed.
Anderson
Alexandra A
AA
Division of Cell and Molecular Biology, Imperial College London, London, UK.
Child
Emma S
ES
Prasad
Aarathi
A
Elphick
Lucy M
LM
Mann
David J
DJ
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D041701:Swiss 3T3 Cells; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014162:Transfection
C534696:CCND3 protein, human; C530105:Ccnd1 protein, mouse; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; D020536:Enzyme Activators; D047908:Intracellular Signaling Peptides and Proteins; D008934:Mitogens; D047428:Protein Kinase Inhibitors; D019938:Cyclin D1; D005576:Colforsin; D015240:Phorbol 12,13-Dibutyrate; D000242:Cyclic AMP; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D020928:Mitogen-Activated Protein Kinases; D020123:Sirolimus