Su W C, Kitagawa M, Xue N, Xie B, Garofalo S, Cho J, Deng C, Horton W A, Fu X Y
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA.
Nature. 1997 Mar 20;386(6622):288-92. doi: 10.1038/386288a0.
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.
软骨发育不全类的软骨发育异常包括人类最常见的侏儒症遗传形式，其中有软骨发育不全、低软骨发育不全以及致死性骨发育不全I型和II型（TDI和TDII），这些是由成纤维细胞生长因子受体FGFR3中的不同突变引起的（参考文献1）。这些与FGFR3相关的生长异常的分子机制和介质尚不清楚。在此我们表明，突变型TDII FGFR3具有组成型酪氨酸激酶活性，可特异性激活转录因子Stat1（信号转导和转录激活因子）。此外，TDII FGFR3的表达诱导了Stat1的核转位、细胞周期抑制剂p21（WAF1/CIP1）的表达以及细胞生长停滞。因此，TDII FGFR3可能利用Stat1作为骨发育中生长迟缓的介质。与此一致的是，在TDII胎儿的软骨细胞中发现了Stat1激活和p21（WAF1/CIP1）表达增加，而在正常胎儿的软骨细胞中未发现。因此，TDII突变受体引起的异常STAT激活和p21（WAF1/CIP1）表达可能是这种与FGFR3相关的骨病的原因。
