Journal Article

Cell cycle, CDKs and cancer: a changing paradigm

Malumbres, Marcos, Barbacid, Mariano

2009

Overview

Key Points Cell cycle deregulation is a common feature of human cancer. Cancer cells frequently display unscheduled proliferation, genomic instability (increased DNA mutations and chromosomal aberrations) and chromosomal instability (changes in chromosome number). The mammalian cell cycle is controlled by a subfamily of cyclin-dependent kinases (CDKs), the activity of which is modulated by several activators (cyclins) and inhibitors (Ink4, and Cip and Kip inhibitors). The activity of cell cycle CDKs is deregulated in cancer cells owing to genetic or epigenetic changes in either CDKs, their regulators or upstream mitogenic pathways. Recent genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. By contrast, CDK1 is essential for cell division in the embryo. Moreover, CDK1 is sufficient among the cell cycle CDKs for driving the cell cycle in all cell types, at least until mid gestation. Constitutive and deregulated CDK activation may contribute not only to unscheduled proliferation but also to genomic and chromosomal instability in cancer cells. The alteration of the DNA damage and mitotic checkpoints frequently results in increased CDK activity that drives tumour cell cycles. Emerging evidence suggests that tumour cells may also have specific requirements for individual CDKs. Therapeutic strategies based on CDK inhibition should take into consideration these specific requirements. For instance, CDK4 is dispensable for mammary gland development, but is required for the development of mammary gland tumours initiated by specific oncogenes such as Erbb2 , Hras or Myc depending on cellular context. Misregulation of cyclin-dependent kinases (CDKs) can induce unscheduled proliferation and genomic and chromosomal instability. How has recent genetic evidence changed our understanding of the roles of CDKs in the cell cycle of normal and tumour cells? Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Care and treatment / Cell Cycle / Cell Proliferation / Chromosomal Instability / Chromosome Aberrations / Cyclin D / Cyclin E - physiology / Cyclin-Dependent Kinases - antagonists & inhibitors / Cyclin-Dependent Kinases - physiology / Cyclins - physiology / DNA Damage / Genetic aspects / Humans / Mitosis / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - pathology / Neoplastic Stem Cells - cytology / Physiological aspects / Protein Kinase Inhibitors - therapeutic use / Protein kinases / review-article