Journal
JOURNAL OF CELL BIOLOGY
Volume 167, Issue 5, Pages 925-934Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200409187
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Funding
- NIA NIH HHS [R01 AG020208, AG20208] Funding Source: Medline
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The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2 a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27(KIPl), thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27(KIP1) perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27(KIP1) expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27(KIP1), and these processes are disrupted in osteosarcoma.
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