The requirement for cyclin D function in tumor maintenance.
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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Yoon Jong
YJ
Choi
Xiaoyu
X
Li
Per
P
Hydbring
Takaomi
T
Sanda
Joanna
J
Stefano
Amanda L
AL
Christie
Sabina
S
Signoretti
A Thomas
AT
Look
Andrew L
AL
Kung
Harald
H
von Boehmer
Piotr
P
Sicinski
D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D056741:Cyclin D / Q000037:antagonists & inhibitors / Q000502:physiology*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000209:etiology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000209:etiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis
D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse