A splice variant of cyclin D2 regulates cardiomyocyte cell cycle through a novel protein aggregation pathway.
The mammalian heart lacks intrinsic ability to replace diseased myocardium with newly divided myocytes. There is scant information on mechanisms regulating cell cycle exit in cardiomyocytes. We cloned a splice variant of cyclin D2 (D2SV) from the mouse heart and found a novel role for this protein in cardiomyocyte cell cycle exit. We report that D2SV is highly expressed in embryonic myocardium compared with the adult heart. Localization studies indicate that D2SV is retained in the endoplasmic reticulum (ER), Golgi and lysosomal compartments and subjected to ER-stress-associated protein aggregation. D2SV aggregation relies on the motor activities of dynein and is blocked by ER stress modulators. The ability of D2SV to sequester other cell cycle proteins provides a mechanistic explanation for its effects on cardiomyocyte cell cycle. We show that D2SV-induced cell cycle exit can be rescued by overexpression of D-type and B-type cyclins. We suggest that protein aggregation may be a major block for cardiomyocyte cell cycle reactivation.
Sun
Qian
Q
Department of Pharmacology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, NS, B3H 1X5 Canada.
Zhang
Feixiong
F
Wafa
Karim
K
Baptist
Timothy
T
Pasumarthi
Kishore B S
KB
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D003001:Cloning, Molecular; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D056742:Cyclin D2; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006056:Golgi Apparatus / Q000378:metabolism; D006321:Heart / Q000196:embryology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection
C534700:Ccnb1 protein, mouse; C486196:Ccnd2 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D056742:Cyclin D2; D016213:Cyclins; D020033:Protein Isoforms; D051742:Transcription Factor CHOP; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D004398:Dyneins