The requirement for cyclin D function in tumor maintenance.

Abstract

D-cyclins represent components of cell cycle machinery. To test the efficacy of targeting D-cyclins in cancer treatment, we engineered mouse strains that allow acute and global ablation of individual D-cyclins in a living animal. Ubiquitous shutdown of cyclin D1 or inhibition of cyclin D-associated kinase activity in mice bearing ErbB2-driven mammary carcinomas triggered tumor cell senescence, without compromising the animals' health. Ablation of cyclin D3 in mice bearing Notch1-driven T cell acute lymphoblastic leukemias (T-ALL) triggered tumor cell apoptosis. Such selective killing of leukemic cells can also be achieved by inhibiting cyclin D associated kinase activity in mouse and human T-ALL models. Inhibition of cyclin D-kinase activity represents a highly-selective anticancer strategy that specifically targets cancer cells without significantly affecting normal tissues.

• Authors: Yoon Jong Choi, Xiaoyu Li, Per Hydbring, Takaomi Sanda, Joanna Stefano, Amanda L Christie, Sabina Signoretti, A Thomas Look, Andrew L Kung, Harald von Boehmer, Piotr Sicinski
• Journal: Cancer cell (Cancer Cell) Vol. 22 Issue 4 Pg. 438-51 (Oct 16 2012) ISSN: 1878-3686 [Electronic] United States
• PMID: 23079655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Cyclin D
• Erbb2 protein, mouse
• Receptor, ErbB-2
• Cyclin-Dependent Kinase 4

Topics

• Animals
• Apoptosis
• Cell Cycle Checkpoints
• Cyclin D (antagonists & inhibitors, physiology)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Female
• Humans
• Mammary Neoplasms, Experimental (etiology)
• Mice
• Neoplasms (drug therapy, etiology, pathology)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, etiology)
• Receptor, ErbB-2 (analysis)