The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention

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Abstract

Cyclin D1 is an important regulator of cell cycle progression and can function as a transcriptionl co-regulator. The overexpression of cyclin D1 has been linked to the development and progression of cancer. Deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. Recent findings have identified novel mechanisms involved in the regulation of cyclin D1 stability. A number of therapeutic agents have been shown to induce cyclin D1 degradation. The therapeutic ablation of cyclin D1 may be useful for the prevention and treatment of cancer. In this review, current knowledge on the regulation of cyclin D1 degradation is discussed. Novel insights into cyclin D1 degradation are also discussed in the context of ablative therapy. A number of unresolved questions regarding the regulation of cellular cyclin D1 levels are also addressed.

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Most cited references 137

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E J Brown, M Albers, T Shin … (1994)

The structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways. FKBP12-rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma, liver and T cells as well as in yeast, and interferes with mitogenic signalling pathways that are involved in G1 progression, namely with activation of the protein p70S6k (refs 5, 11-13) and cyclin-dependent kinases. Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly, these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases.

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Curcumin: the story so far.

R A Sharma, A Gescher, W Steward (2005)

Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric. It possesses diverse anti-inflammatory and anti-cancer properties following oral or topical administration. Apart from curcumin's potent antioxidant capacity at neutral and acidic pH, its mechanisms of action include inhibition of several cell signalling pathways at multiple levels, effects on cellular enzymes such as cyclooxygenase and glutathione S-transferases, immuno-modulation and effects on angiogenesis and cell-cell adhesion. Curcumin's ability to affect gene transcription and to induce apoptosis in preclinical models is likely to be of particular relevance to cancer chemoprevention and chemotherapy in patients. Although curcumin's low systemic bioavailability following oral dosing may limit access of sufficient concentrations for pharmacological effect in certain tissues, the attainment of biologically active levels in the gastrointestinal tract has been demonstrated in animals and humans. Sufficient data currently exist to advocate phase II clinical evaluation of oral curcumin in patients with invasive malignancy or pre-invasive lesions of the gastrointestinal tract, particularly the colon and rectum.

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Journal

Journal ID (nlm-ta): Mol Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date Collection: 2007

Publication date (Electronic): 2 April 2007

Volume: 6

Page: 24

Affiliations

[1 ]Department of Cell and Molecular Biology, Lundberg Laboratory, Gothenburg University, P. O. Box 462, S-405 30, Gothenburg, Sweden

Article

Publisher ID: 1476-4598-6-24

DOI: 10.1186/1476-4598-6-24

PMC ID: 1851974

PubMed ID: 17407548

SO-VID: 56fafdb9-8ef7-4aba-b8d5-a8165d9d9c2a

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention

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Karger: Oncology

Most cited references 137

Cellular survival: a play in three Akts.

A mammalian protein targeted by G1-arresting rapamycin-receptor complex.

Curcumin: the story so far.

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