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Molecular and Cellular Biology Volume 34, 2014 - Issue 12
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Article

Loss of the Mammalian DREAM Complex Deregulates Chondrocyte Proliferation

Chantal Forristala London Regional Cancer Program, Western University, London, Ontario, Canada;c Department of Biochemistry, Western University, London, Ontario, Canada
,
Shauna A. Henleya London Regional Cancer Program, Western University, London, Ontario, Canada;c Department of Biochemistry, Western University, London, Ontario, Canada
,
James I. MacDonalda London Regional Cancer Program, Western University, London, Ontario, Canada;c Department of Biochemistry, Western University, London, Ontario, Canada
,
Jason R. Bushb Children's Health Research Institute, Western University, London, Ontario, Canada;d Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
,
Carley Ortd Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
,
Daniel T. Passosa London Regional Cancer Program, Western University, London, Ontario, Canada;c Department of Biochemistry, Western University, London, Ontario, Canada
,
Srikanth Talluria London Regional Cancer Program, Western University, London, Ontario, Canada;c Department of Biochemistry, Western University, London, Ontario, Canada
,
Charles A. Ishaka London Regional Cancer Program, Western University, London, Ontario, Canada;c Department of Biochemistry, Western University, London, Ontario, Canada
,
Michael J. Thwaitesa London Regional Cancer Program, Western University, London, Ontario, Canada;c Department of Biochemistry, Western University, London, Ontario, Canada
,
Chris J. Norleye Department of Medical Biophysics, Western University, London, Ontario, Canada
,
Larisa Litovchickg Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
,
James A. DeCaprioh Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA;i Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
,
Gabriel DiMattiaa London Regional Cancer Program, Western University, London, Ontario, Canada;c Department of Biochemistry, Western University, London, Ontario, Canada;f Department of Oncology, Western University, London, Ontario, Canada
,
David W. Holdsworthe Department of Medical Biophysics, Western University, London, Ontario, Canada
,
Frank Beierb Children's Health Research Institute, Western University, London, Ontario, Canada;d Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
&
Frederick A. Dicka London Regional Cancer Program, Western University, London, Ontario, Canada;b Children's Health Research Institute, Western University, London, Ontario, Canada;c Department of Biochemistry, Western University, London, Ontario, Canada;f Department of Oncology, Western University, London, Ontario, CanadaCorrespondence[email protected]
 show all
Pages 2221-2234 | Received 18 Nov 2013, Accepted 27 Mar 2014, Published online: 20 Mar 2023
 
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Abstract

Mammalian DREAM is a conserved protein complex that functions in cellular quiescence. DREAM contains an E2F, a retinoblastoma (RB)-family protein, and the MuvB core (LIN9, LIN37, LIN52, LIN54, and RBBP4). In mammals, MuvB can alternatively bind to BMYB to form a complex that promotes mitotic gene expression. Because BMYB-MuvB is essential for proliferation, loss-of-function approaches to study MuvB have generated limited insight into DREAM function. Here, we report a gene-targeted mouse model that is uniquely deficient for DREAM complex assembly. We have targeted p107 (Rbl1) to prevent MuvB binding and combined it with deficiency for p130 (Rbl2). Our data demonstrate that cells from these mice preferentially assemble BMYB-MuvB complexes and fail to repress transcription. DREAM-deficient mice show defects in endochondral bone formation and die shortly after birth. Micro-computed tomography and histology demonstrate that in the absence of DREAM, chondrocytes fail to arrest proliferation. Since DREAM requires DYRK1A (dual-specificity tyrosine phosphorylation-regulated protein kinase 1A) phosphorylation of LIN52 for assembly, we utilized an embryonic bone culture system and pharmacologic inhibition of (DYRK) kinase to demonstrate a similar defect in endochondral bone growth. This reveals that assembly of mammalian DREAM is required to induce cell cycle exit in chondrocytes.

ACKNOWLEDGMENTS

We are indebted to many colleagues for discussions and encouragement during the course of this work.

C.F. was supported by an SRP award from the Schulich School of Medicine and Dentistry. S.A.H. and C.A.I. were supported by fellowship awards from CaRTT, and S.A.H. also acknowledges fellowship support from CBCF-Ontario. J.R.B. is the recipient of CIHR postdoctoral fellowship (Priority Announcement: Epigenetics). F.B. is the Canada Research Chair in musculoskeletal research. F.A.D. is the Wolfe Senior Fellow in Tumor Suppressor Genes at Western University. Funding for this work was provided by the Canadian Cancer Society Research Institute (2011-700720) to F.A.D. and the Canadian Institutes of Health Research (MOP43899) to F.B.

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