Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism

Wu Chou S Su, Motoo Kitagawa, Ninrong Xue, Bing Xie, Silvio Garofalo, Jay Cho, Chuxia Deng, William A. Horton, Xin Yuan Fu

Research output: Contribution to journalArticle

251 Citations (Scopus)

Abstract

The achondroplasia class of chondrodysplasias comprises the most common genetic forms of dwarfism in humans and includes achondroplasia, hypochondroplasia and thanatophoric dysplasia types I and II (TDI and TDII), which are caused by different mutations in a fibroblast growth-factor receptor FGFR3 (ref.1). The molecular mechanism and the mediators of these FGFR3-related growth abnormalities are not known. Here we show that mutant TDII FGFR3 has a constitutive tyrosine kinase activity which can specifically activate the transcription factor Stat1 (for signal transducer and activator of transcription). Furthermore, expression of TDII FGFR3 induced nuclear translocation of Stat1, expression of the cell-cycle inhibitor p21(WAF1/CIP1), and growth arrest of the cell. Thus, TDII FGFR3 may use Stat1 as a mediator of growth retardation in bone development. Consistent with this, Stat1 activation and increased p21(WAF1/CIP1) expression was found in the cartilage cells from the TDII fetus, but not in those from the normal fetus. Thus, abnormal STAT activation and p21(WAF1/CIP1) expression by the TDII mutant receptor may be responsible for this FGFR3-related bone disease.

Original languageEnglish (US)
Pages (from-to)288-292
Number of pages5
JournalNature
Volume386
Issue number6622
DOIs
StatePublished - Mar 20 1997
Externally publishedYes

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Thanatophoric Dysplasia
Dwarfism
Fibroblast Growth Factor Receptors
Achondroplasia
Fetus
Growth
Enchondromatosis
Bone Diseases
Bone Development
Transducers
Protein-Tyrosine Kinases
Cartilage
Cell Cycle
Transcription Factors
Mutation

ASJC Scopus subject areas

  • General

Cite this

Su, W. C. S., Kitagawa, M., Xue, N., Xie, B., Garofalo, S., Cho, J., ... Fu, X. Y. (1997). Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature, 386(6622), 288-292. https://doi.org/10.1038/386288a0

Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. / Su, Wu Chou S; Kitagawa, Motoo; Xue, Ninrong; Xie, Bing; Garofalo, Silvio; Cho, Jay; Deng, Chuxia; Horton, William A.; Fu, Xin Yuan.

In: Nature, Vol. 386, No. 6622, 20.03.1997, p. 288-292.

Research output: Contribution to journalArticle

Su, WCS, Kitagawa, M, Xue, N, Xie, B, Garofalo, S, Cho, J, Deng, C, Horton, WA & Fu, XY 1997, 'Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism', Nature, vol. 386, no. 6622, pp. 288-292. https://doi.org/10.1038/386288a0
Su, Wu Chou S ; Kitagawa, Motoo ; Xue, Ninrong ; Xie, Bing ; Garofalo, Silvio ; Cho, Jay ; Deng, Chuxia ; Horton, William A. ; Fu, Xin Yuan. / Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. In: Nature. 1997 ; Vol. 386, No. 6622. pp. 288-292.
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