© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Arresting developments in the cardiac myocyte cell cycle: Role of cyclin-dependent kinase inhibitors
aCardiovascular Cell and Molecular Biology Laboratory, Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, UK
bProlifix Ltd., 91 Milton Park, Abingdon, Oxon, OX14 4RY, UK
* Corresponding author. Prolifix Ltd., 91 Milton Park, Abingdon, Oxon, OX14 4RY, UK. Tel: 00-44-1235-443 726; Fax: 00-44-1235-443 744; E-mail: g.brooks@prolifix.co.uk
Like most other cells in the body, foetal and neonatal cardiac myocytes are able to divide and proliferate. However, the ability of these cells to undergo cell division decreases progressively during development such that adult myocytes are unable to divide. A major problem arising from this inability of adult cardiac myocytes to proliferate is that the mature heart is unable to regenerate new myocardial tissue following severe injury, e.g. infarction, which can lead to compromised cardiac pump function and even death. Studies in proliferating cells have identified a group of genes and proteins that controls cell division. These proteins include cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs), which interact with each other to form complexes that are essential for controlling normal cell cycle progression. A variety of other proteins, e.g. the retinoblastoma protein (pRb) and members of the E2F family of transcription factors, also can interact with, and modulate the activities of, these complexes. Despite the major role that these proteins play in other cell types, little was known until recently about their existence and activities in immature (proliferating) or mature (non-proliferating) cardiac myocytes. The reason(s) why cardiac myocytes lose their ability to divide during development remains unknown, but if strategies were developed to understand the mechanisms underlying cardiac myocyte growth, it could open up new avenues for the treatment of cardiovascular disease. In this article, we shall review the function of the cell cycle machinery and outline some of our recent findings pertaining to the involvement of the cell cycle in modulating cardiac myocyte growth and hypertrophy.
KEYWORDS CDK, cyclin-dependent kinase; CDKI, cyclin-dependent kinase inhibitor; pRb, retinoblastoma protein; LVH, left ventricular hypertrophy; R point, restriction point; TGF-β, transforming growth factor-β; MTS, multiple tumour suppressor; AC, aortic constriction; SH, sham; LV, left ventricular; FACS, fluorescence-activated cell sorting; mRNA, messenger ribonucleic acid; PCNA, proliferating cell nuclear antigen
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