Gli2 and p53 cooperate to regulate IGFBP-3- mediated chondrocyte apoptosis in the progression from benign to malignant cartilage tumors.
Clinical evidence suggests that benign cartilage lesions can progress to malignant chondrosarcoma, but the molecular events in this progression are unknown. Mice that develop benign cartilage lesions due to overexpression of Gli2 in chondrocytes developed lesions similar to chondrosarcomas when they were also deficient in p53. Gli2 overexpression and p53 deficiency had opposing effects on chondrocyte differentiation, but had additive effects negatively regulating apoptosis. Regulation of Igfbp3 expression and insulin-like growth factor (IGF) signaling by Gli and p53 integrated their effect on apoptosis. Treatment of human chondrosarcomas or fetal mouse limb explants with IGFBP3 or by blocking IGF increased the apoptosis rate, and mice expressing Gli2 developed substantially fewer tumors when they were also deficient for Igf2. IGF signaling-meditated apoptosis regulates the progression to malignant chondrosarcoma.
Ho
Louisa
L
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, ON, Canada.
Stojanovski
Aneta
A
Whetstone
Heather
H
Wei
Qing Xia
QX
Mau
Elaine
E
Wunder
Jay S
JS
Alman
Benjamin
B
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000473:pathology*; D002813:Chondrosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D024121:Collagen Type X / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006132:Growth Plate / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000075746:Zinc Finger Protein Gli2
D024121:Collagen Type X; C000618551:Gli2 protein, mouse; D018972:Insulin-Like Growth Factor Binding Protein 3; D051741:Kruppel-Like Transcription Factors; D013002:Somatomedins; D016159:Tumor Suppressor Protein p53; D000075746:Zinc Finger Protein Gli2