Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfβ in osteosarcoma cells

Inga A. San Martin, Nelson Varela, Marcia Gaete, Karina Villegas, Mariana Osorio, Julio C. Tapia, Marcelo Antonelli, Edna E. Mancilla, Barry P. Pereira, Saminathan S. Nathan, Jane B. Lian, Janet L. Stein, Gary S. Stein, Andre J van Wijnen, Mario Galindo

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Bone formation and osteoblast differentiation require the functional expression of the Runx2/Cbfβ heterodimeric transcription factor complex. Runx2 is also a suppressor of proliferation in osteoblasts by attenuating cell cycle progression in G1. Runx2 levels are modulated during the cell cycle, which are maximal in G1 and minimal beyond the G1/S phase transition (S, G2, and M phases). It is not known whether Cbfβ gene expression is cell cycle controlled in preosteoblasts nor how Runx2 or Cbfβ are regulated during the cell cycle in bone cancer cells. We investigated Runx2 and Cbfβ gene expression during cell cycle progression in MC3T3-E1 osteoblasts, as well as ROS17/2.8 and SaOS-2 osteosarcoma cells. Runx2 protein levels are reduced as expected in MC3T3-E1 cells arrested in late G1 (by mimosine) or M phase (by nocodazole), but not in cell cycle arrested osteosarcoma cells. Cbfβ protein levels are cell cycle independent in both osteoblasts and osteosarcoma cells. In synchronized MC3T3-E1 osteoblasts progressing from late G1 or mitosis, Runx2 levels but not Cbfβ levels are cell cycle regulated. However, both factors are constitutively elevated throughout the cell cycle in osteosarcoma cells. Proteasome inhibition by MG132 stabilizes Runx2 protein levels in late G 1 and S in MC3T3-E1 cells, but not in ROS17/2.8 and SaOS-2 osteosarcoma cells. Thus, proteasomal degradation of Runx2 is deregulated in osteosarcoma cells. We propose that cell cycle control of Runx2 gene expression is impaired in osteosarcomas and that this deregulation may contribute to the pathogenesis of osteosarcoma.

Original languageEnglish (US)
Pages (from-to)560-571
Number of pages12
JournalJournal of Cellular Physiology
Volume221
Issue number3
DOIs
StatePublished - Dec 2009
Externally publishedYes

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Osteoblasts
Osteosarcoma
Cell Cycle
Transcription Factors
Cells
Core Binding Factor Alpha 1 Subunit
Gene expression
G1 Phase
S Phase
Gene Expression
Cell Division
Mimosine
Bone
Nocodazole
Bone Neoplasms
Cell Cycle Proteins
G2 Phase
Phase Transition
Proteasome Endopeptidase Complex
Cell Cycle Checkpoints

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

San Martin, I. A., Varela, N., Gaete, M., Villegas, K., Osorio, M., Tapia, J. C., ... Galindo, M. (2009). Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfβ in osteosarcoma cells. Journal of Cellular Physiology, 221(3), 560-571. https://doi.org/10.1002/jcp.21894

Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfβ in osteosarcoma cells. / San Martin, Inga A.; Varela, Nelson; Gaete, Marcia; Villegas, Karina; Osorio, Mariana; Tapia, Julio C.; Antonelli, Marcelo; Mancilla, Edna E.; Pereira, Barry P.; Nathan, Saminathan S.; Lian, Jane B.; Stein, Janet L.; Stein, Gary S.; van Wijnen, Andre J; Galindo, Mario.

In: Journal of Cellular Physiology, Vol. 221, No. 3, 12.2009, p. 560-571.

Research output: Contribution to journalArticle

San Martin, IA, Varela, N, Gaete, M, Villegas, K, Osorio, M, Tapia, JC, Antonelli, M, Mancilla, EE, Pereira, BP, Nathan, SS, Lian, JB, Stein, JL, Stein, GS, van Wijnen, AJ & Galindo, M 2009, 'Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfβ in osteosarcoma cells', Journal of Cellular Physiology, vol. 221, no. 3, pp. 560-571. https://doi.org/10.1002/jcp.21894
San Martin, Inga A. ; Varela, Nelson ; Gaete, Marcia ; Villegas, Karina ; Osorio, Mariana ; Tapia, Julio C. ; Antonelli, Marcelo ; Mancilla, Edna E. ; Pereira, Barry P. ; Nathan, Saminathan S. ; Lian, Jane B. ; Stein, Janet L. ; Stein, Gary S. ; van Wijnen, Andre J ; Galindo, Mario. / Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfβ in osteosarcoma cells. In: Journal of Cellular Physiology. 2009 ; Vol. 221, No. 3. pp. 560-571.
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abstract = "Bone formation and osteoblast differentiation require the functional expression of the Runx2/Cbfβ heterodimeric transcription factor complex. Runx2 is also a suppressor of proliferation in osteoblasts by attenuating cell cycle progression in G1. Runx2 levels are modulated during the cell cycle, which are maximal in G1 and minimal beyond the G1/S phase transition (S, G2, and M phases). It is not known whether Cbfβ gene expression is cell cycle controlled in preosteoblasts nor how Runx2 or Cbfβ are regulated during the cell cycle in bone cancer cells. We investigated Runx2 and Cbfβ gene expression during cell cycle progression in MC3T3-E1 osteoblasts, as well as ROS17/2.8 and SaOS-2 osteosarcoma cells. Runx2 protein levels are reduced as expected in MC3T3-E1 cells arrested in late G1 (by mimosine) or M phase (by nocodazole), but not in cell cycle arrested osteosarcoma cells. Cbfβ protein levels are cell cycle independent in both osteoblasts and osteosarcoma cells. In synchronized MC3T3-E1 osteoblasts progressing from late G1 or mitosis, Runx2 levels but not Cbfβ levels are cell cycle regulated. However, both factors are constitutively elevated throughout the cell cycle in osteosarcoma cells. Proteasome inhibition by MG132 stabilizes Runx2 protein levels in late G 1 and S in MC3T3-E1 cells, but not in ROS17/2.8 and SaOS-2 osteosarcoma cells. Thus, proteasomal degradation of Runx2 is deregulated in osteosarcoma cells. We propose that cell cycle control of Runx2 gene expression is impaired in osteosarcomas and that this deregulation may contribute to the pathogenesis of osteosarcoma.",
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AU - San Martin, Inga A.

AU - Varela, Nelson

AU - Gaete, Marcia

AU - Villegas, Karina

AU - Osorio, Mariana

AU - Tapia, Julio C.

AU - Antonelli, Marcelo

AU - Mancilla, Edna E.

AU - Pereira, Barry P.

AU - Nathan, Saminathan S.

AU - Lian, Jane B.

AU - Stein, Janet L.

AU - Stein, Gary S.

AU - van Wijnen, Andre J

AU - Galindo, Mario

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