Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma.
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.
Thomas
David M
DM
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
Johnson
Sandra A
SA
Sims
Natalie A
NA
Trivett
Melanie K
MK
Slavin
John L
JL
Rubin
Brian P
BP
Waring
Paul
P
McArthur
Grant A
GA
Walkley
Carl R
CR
Holloway
Andrew J
AJ
Diyagama
Dileepa
D
Grim
Jonathon E
JE
Clurman
Bruce E
BE
Bowtell
David D L
DD
Lee
Jong-Seo
JS
Gutierrez
Gabriel M
GM
Piscopo
Denise M
DM
Carty
Shannon A
SA
Hinds
Philip W
PW
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018816:Genes, cdc / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010006:Osteoblasts / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C436291:CDKN1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D016213:Cyclins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018809:Proliferating Cell Nuclear Antigen; C493709:RUNX2 protein, human; D016160:Retinoblastoma Protein; C493716:Runx2 protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D015675:Osteocalcin; D050760:Cyclin-Dependent Kinase Inhibitor p27