To cycle or not to cycle: a critical decision in cancer View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2001-12

AUTHORS

Marcos Malumbres, Mariano Barbacid

ABSTRACT

Key PointsThe cell cycle is regulated by cyclin-dependent kinases (CDKs), which form active heterodimeric kinases when bound to the cyclins. Active CDK–cyclin complexes can be negatively regulated by two families of inhibitors, the INK4 and the WAF1/KIP proteins. The CDK4/6–cyclin-D and CDK2–cyclin-E complexes are active in G1, and CDK2–cyclin-A and CDK1–cyclin-A are active in S phase. The CDK complex responsible for driving cells through mitosis is CDK1–cyclin B. The main G1 substrates of CDKs are the retinoblastoma family (RB, p107 and p130). RB is sequentially phosphorylated by CDK4/6–cyclin-D and CDK2–cyclin-E complexes. This phosphorylation inactivates the growth-suppression properties of RB and stimulates progression through G1 and into S phase. The basic regulators of G1 progression are altered in most human cancers. Genetic alterations usually affect CDK4 and CDK6, their positive (mainly cyclin D1) and negative (INK4A and INK4B) regulators and their substrates (mainly RB). Deregulation of CDK2 activity frequently results from the alteration in the expression levels of its regulators cyclin E and KIP1. The cause of these alterations is not clear. Recently, some members of the proteolysis pathways involved in the control of cyclin E and KIP1 protein levels have been found to be altered in certain types of cancer. A few other cell-cycle regulators, mostly those involved in the mitotic spindle checkpoint, are also deregulated in human cancer. They include BUB proteins, MAD2, the Aurora kinases, PLK1 and securin. The evidence for their involvement in human cancer is, so far, scarce. The generation of gene-targeted mice has illustrated the importance of G1 regulators in tumour development. Although most of these are not essential for cell-cycle progression or mouse development, their deregulation often leads to tumour development. The understanding of G1 regulation has opened new avenues to search for antitumor drugs. Although there are several ways to control CDK activity, small-molecule CDK inhibitors are the preferred tools, at this time. So far, several CDK inhibitors (mainly CDK2 and pan-CDK inhibitors) are in advanced preclinical studies and at least two of them — flavopiridol and UCN-01 — have reached clinical trials. More... »

PAGES

222-231

References to SciGraph publications

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  • Journal

    TITLE

    Nature Reviews Cancer

    ISSUE

    3

    VOLUME

    1

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/35106065

    DOI

    http://dx.doi.org/10.1038/35106065

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1029289076

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/11902577


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