Expression levels of insulin receptor substrate-1 modulate the osteoblastic differentiation of mesenchymal stem cells and osteosarcoma cells.
The insulin-like growth factor-1 system, including its critical mediator insulin receptor substrate-1 (IRS-1), is involved in regulating osteosarcoma (OS) cell proliferation or differentiation. The aim of this study is to define the role of IRS-1 in OS cells by assessing the contribution of IRS-1 in the differentiation of human and murine OS cell lines and mouse mesenchymal stem cells (MSCs) and found that the basal level of IRS-1 is important for the initiation of differentiation. Both down-regulation and over-expression of IRS-1 inhibited osteoblastic differentiation. In vivo studies showed that OS cells over-expressing IRS-1 have increased metastatic potential and tumor growth. The proteasome inhibitor MG-132 led to an increase in IRS-1 protein level that inhibited osteoblastic differentiation, suggesting a role for proteasomal regulation in maintaining the appropriate expression level of IRS-1. Thus, precise regulation of IRS-1 expression level is critical for determining the differentiating capacity of MSCs and OS cells, and that derangement of IRS-1 levels can be a critical step in OS transformation.
Laboratory of Experimental Oncology, CRS Development of Molecular Therapies, Orthopaedic Rizzoli Institute , Bologna , Italy .
Clara
C
Contaldo
Timothy J
TJ
Myers
Cinzia
C
Zucchini
Maria Cristina
MC
Manara
Claudia
C
Chiodoni
Mario P
MP
Colombo
Giordano
G
Nicoletti
Pier Luigi
PL
Lollini
Tieshi
T
Li
Lara
L
Longobardi
Katia
K
Scotlandi
Anna
A
Spagnoli
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D010006:Osteoblasts / Q000378:metabolism*; D015675:Osteocalcin / Q000096:biosynthesis; D012516:Osteosarcoma / Q000473:pathology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000096:biosynthesis
D015853:Cysteine Proteinase Inhibitors; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D007976:Leupeptins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; C519530:insulin-like growth factor-1, mouse; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde