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Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma.

Thomas DM, Johnson SA, Sims NA, Trivett MK, Slavin JL, Rubin BP, Waring P, McArthur GA, Walkley CR, Holloway AJ, Diyagama D, Grim JE, Clurman BE, Bowtell DD, Lee JS, Gutierrez GM, Piscopo DM, Carty SA, Hinds PW - J. Cell Biol. (2004)

Bottom Line: Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts.Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas.Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.

View Article: PubMed Central - PubMed

Affiliation: Ian Potter Foundation Centre for Cancer Genomics and Predictive Medicine, and Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Center, Victoria, Melbourne, Australia. david.thomas@petermac.org

ABSTRACT
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 p27KIP1, 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 p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.

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A model for interactions between cell cycle proteins and runx2 in osteoblasts. The interaction of hypophosphorylated pRB with runx2 completes a positive feedback loop, promoting cell cycle withdrawal and expression of the osteoblast phenotype. See Discussion section.
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fig8: A model for interactions between cell cycle proteins and runx2 in osteoblasts. The interaction of hypophosphorylated pRB with runx2 completes a positive feedback loop, promoting cell cycle withdrawal and expression of the osteoblast phenotype. See Discussion section.

Mentions: The inverse relationship between proliferation and differentiation in osteoblasts has been carefully documented for many years, although the mechanisms have not been delineated. These observations have led to the proposition that full expression of the osteoblast phenotype is necessarily associated with terminal cell cycle exit (Stein et al., 1996; Aubin, 1998). In accord with these observations, osteoblasts lacking functional runx2 appear to lose a growth restraint (Pratap et al., 2003). Our data provide a mechanistic basis for these observations (Fig. 8). Osteogenic differentiation in culture imposes a growth restraint and, eventually, a terminal cell cycle exit resembling senescence, through runx2-dependent induction of p27KIP1. We and others show that osteogenic differentiation in vitro is associated with increased expression of p27KIP1 (Drissi et al., 1999). This leads to a pRb-dependent growth arrest through inhibition of S-phase cyclin complexes. We have shown previously that interactions between runx2 and pRb enhance runx2-dependent transcriptional activity (Thomas et al., 2001). Because it is the hypophosphorylated form of pRb that binds runx2, the induction of p27KIP1 will enhance the transactivation of runx2 by pRb, leading to progressive growth arrest and expression of the mature osteoblast phenotype (Fig. 8). It is likely that loss of function of any component of this feed-forward loop will disrupt both differentiation and a restraint on cell growth. Although mutations have been documented in pRb in osteosarcoma, the molecular events that affect runx2 function in cell lines in which pRb is not affected remain unknown.


Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma.

Thomas DM, Johnson SA, Sims NA, Trivett MK, Slavin JL, Rubin BP, Waring P, McArthur GA, Walkley CR, Holloway AJ, Diyagama D, Grim JE, Clurman BE, Bowtell DD, Lee JS, Gutierrez GM, Piscopo DM, Carty SA, Hinds PW - J. Cell Biol. (2004)

A model for interactions between cell cycle proteins and runx2 in osteoblasts. The interaction of hypophosphorylated pRB with runx2 completes a positive feedback loop, promoting cell cycle withdrawal and expression of the osteoblast phenotype. See Discussion section.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172443&req=5

fig8: A model for interactions between cell cycle proteins and runx2 in osteoblasts. The interaction of hypophosphorylated pRB with runx2 completes a positive feedback loop, promoting cell cycle withdrawal and expression of the osteoblast phenotype. See Discussion section.
Mentions: The inverse relationship between proliferation and differentiation in osteoblasts has been carefully documented for many years, although the mechanisms have not been delineated. These observations have led to the proposition that full expression of the osteoblast phenotype is necessarily associated with terminal cell cycle exit (Stein et al., 1996; Aubin, 1998). In accord with these observations, osteoblasts lacking functional runx2 appear to lose a growth restraint (Pratap et al., 2003). Our data provide a mechanistic basis for these observations (Fig. 8). Osteogenic differentiation in culture imposes a growth restraint and, eventually, a terminal cell cycle exit resembling senescence, through runx2-dependent induction of p27KIP1. We and others show that osteogenic differentiation in vitro is associated with increased expression of p27KIP1 (Drissi et al., 1999). This leads to a pRb-dependent growth arrest through inhibition of S-phase cyclin complexes. We have shown previously that interactions between runx2 and pRb enhance runx2-dependent transcriptional activity (Thomas et al., 2001). Because it is the hypophosphorylated form of pRb that binds runx2, the induction of p27KIP1 will enhance the transactivation of runx2 by pRb, leading to progressive growth arrest and expression of the mature osteoblast phenotype (Fig. 8). It is likely that loss of function of any component of this feed-forward loop will disrupt both differentiation and a restraint on cell growth. Although mutations have been documented in pRb in osteosarcoma, the molecular events that affect runx2 function in cell lines in which pRb is not affected remain unknown.

Bottom Line: Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts.Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas.Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.

View Article: PubMed Central - PubMed

Affiliation: Ian Potter Foundation Centre for Cancer Genomics and Predictive Medicine, and Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Center, Victoria, Melbourne, Australia. david.thomas@petermac.org

ABSTRACT
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 p27KIP1, 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 p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.

Show MeSH
Related in: MedlinePlus