CDK4/6 Dependence of Cyclin D1-Driven Parathyroid Neoplasia in Transgenic Mice.

Autor:	Costa-Guda J; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut.; Center for Regenerative Medicine and Skeletal Development, University of Connecticut School of Dental Medicine, Farmington, Connecticut., Corrado K; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut., Bellizzi J; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut., Romano R; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut., Saria E; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut., Saucier K; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut., Rose M; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut., Shah S; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut., Alander C; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut., Mallya S; Section of Oral and Maxillofacial Radiology, UCLA School of Dentistry, Los Angeles, California., Arnold A; Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, Connecticut.
Jazyk:	angličtina
Zdroj:	Endocrinology [Endocrinology] 2020 Oct 01; Vol. 161 (10).
DOI:	10.1210/endocr/bqaa159
Abstrakt:	The protein product of the cyclin D1 oncogene functions by activating partner cyclin-dependent kinases (cdk)4 or cdk6 to phosphorylate, thereby inactivating, the retinoblastoma protein pRB. Nonclassical, cdk-independent, functions of cyclin D1 have been described but their role in cyclin D1-driven neoplasia, with attendant implications for recently approved cdk4/6 chemotherapeutic inhibitors, requires further examination. We investigated whether cyclin D1's role in parathyroid tumorigenesis in vivo is effected primarily through kinase-dependent or kinase-independent mechanisms. Using a mouse model of cyclin D1-driven parathyroid tumorigenesis (PTH-D1), we generated new transgenic lines harboring a mutant cyclin D1 (KE) that is unable to activate its partner kinases. While this kinase-dead KE mutant effectively drove mammary tumorigenesis in an analogous model, parathyroid-overexpressed cyclin D1 KE mice did not develop the characteristic biochemical hyperparathyroidism or parathyroid hypercellularity of PTH-D1 mice. These results strongly suggest that in parathyroid cells, cyclin D1 drives tumorigenesis predominantly through cdk-dependent mechanisms, in marked contrast with the cdk-independence of cyclin D1-driven mouse mammary cancer. These findings highlight crucial tissue-specific mechanistic differences in cyclin D1-driven tumorigenesis, suggest that parathyroid/endocrine cells may be more tumorigenically vulnerable to acquired genetic perturbations in cdk-mediated proliferative control than other tissues, and carry important considerations for therapeutic intervention. (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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