Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells.
Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells.
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DOI：
10.1002/jcp.21894
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发表时间：
2009-12
影响因子：
5.6
通讯作者：
Galindo, Mario
中科院分区：
文献类型：
--
作者：
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
在哺乳动物中，骨分化需要Runx2/Cbfβ异二聚体复合体的功能性表达。我们之前的研究结果表明，Runx2也是通过影响G1期细胞周期进程来抑制成骨前细胞增殖的。Runx2水平受细胞周期调控，在增殖的成骨前细胞中，从G1早期的最大值到G1晚期、S期和有丝分裂期的最小值振荡。然而，在骨癌细胞中，没有关于Cbfβ基因在细胞周期中的表达和Runx2细胞周期表达的信息。我们分析了Runx2和Cbfβ基因在成骨前MC3T3和骨肉瘤ROS和SaOS细胞系细胞周期进程中的表达。在G1晚期或M期分别使用米莫辛或诺可达唑的MC3T3细胞中观察到Runx2蛋白水平的预期降低。然而，在细胞周期阻滞的骨肉瘤细胞中没有观察到这种减少。在成骨前细胞和骨肉瘤细胞中，Cbfβ蛋白水平在细胞周期中不受调节。在G1晚期和有丝分裂同步的细胞中，我们发现Runx2水平在MC3T3成骨细胞中受细胞周期调节，而Cbfβ水平不受细胞周期调节。有趣的是，这两个因子在骨肉瘤细胞的整个细胞周期中都表现出组成性的表达升高。MG132对蛋白酶体的抑制可以阻止成骨细胞中Runx2蛋白水平的细胞周期依赖性下调，但在骨肉瘤中没有作用。我们认为Runx2参与了肿瘤骨肉瘤的进展。总之，在整个细胞周期中Runx2表达的失调似乎构成了骨肉瘤发病的中心机制。
In mammals, bone differentiation requires the functional expression of the Runx2/Cbfβ heterodimeric complex. Our previous results indicate that Runx2 is also a suppressor of pre-osteoblast proliferation by affecting cell cycle progression at G1. Runx2 levels are cell cycle regulated, oscillating from a maximum during early G1 to a minimum during late G1, S and mitosis phases in proliferating pre-osteoblasts Nevertheless, there is no information concerning Cbfβ gene expression during the cell cycle nor on Runx2 cell cycle expression in bone cancer cells. We analyzed Runx2 and Cbfβ gene expression during cell cycle progression in the pre-osteoblast MC3T3 and osteosarcoma ROS and SaOS cell lines. The expected reduction of Runx2 protein level was observed in MC3T3 cells arrested in late G1 or M phase using mimosine or nocodazole, respectively. However, this reduction was not observed in the cell cycle arrested osteosarcoma cells. Cbfβ protein levels were not regulated during the cell cycle in pre-osteoblasts and osteosarcoma cells. Using cells synchronized in late G1 and mitosis we found that Runx2 levels, but not Cbfβ levels, were cell cycle regulated in MC3T3 osteoblasts. Interestingly, both factors showed a constitutively elevated expression throughout the cell cycle in osteosarcoma cells. Proteasome inhibition by MG132 prevented cell cycle-dependent downregulation of Runx2 protein levels in osteoblasts, but not in osteosarcoma. We propose that Runx2 is involved in tumoral osteosarcoma progression. Altogether, deregulated Runx2 expression throughout the cell cycle seems to constitute a central mechanism in the pathogenesis of osteosarcoma.
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