Magrangeas F, Boisteau O, Denis S, Jacques Y, Minvielle S
INSERM U. 463, Institut de Biologie, 9, quai Moncousu, 44093 Nantes Cedex 01, France.
Eur Cytokine Netw. 2001 Apr-Jun;12(2):309-15.
Oncostatin M (OSM) is known to inhibit the growth of melanocytes and early-stage melanomas, but this ability is lost with melanoma progression. The biological effects of OSM involve the activation of Janus kinases (Jak) and signal transducer and activator of transcription (STAT) factors. Since SOCS (suppressor of cytokine signaling) a recently described family of regulatory proteins, has been shown to act through down-regulation of Jak-STAT signaling, we investigated their putative role in the inhibition of OSM signaling in the human melanoma cell line A375. We observed that, among the SOCS family members examined, only SOCS-3 mRNA was strongly and rapidly induced by OSM. SOCS-3 protein was present within 1h and rapidly declined thereafter. Constitutive expression of SOCS-3 protein completely abolished the activation of the Jak-STAT signaling pathway as well as the Ras-MAP kinase pathway. As a result, A375 cells acquired an OSM-resistant phenotype. Our findings demonstrate that SOCS-3 is a potent regulator of OSM response and suggest that dysregulation of SOCS-3 expression could provide a mechanism for OSM resistance acquisition during tumour progression.
抑瘤素M（OSM）已知可抑制黑素细胞和早期黑色素瘤的生长，但随着黑色素瘤的进展，这种能力会丧失。OSM的生物学效应涉及Janus激酶（Jak）和信号转导及转录激活因子（STAT）的激活。由于细胞因子信号抑制因子（SOCS）是最近描述的一类调节蛋白，已被证明通过下调Jak-STAT信号发挥作用，我们研究了它们在人黑色素瘤细胞系A375中对OSM信号抑制的假定作用。我们观察到，在所检测的SOCS家族成员中，只有SOCS-3 mRNA被OSM强烈且迅速地诱导。SOCS-3蛋白在1小时内出现，随后迅速下降。SOCS-3蛋白的组成型表达完全消除了Jak-STAT信号通路以及Ras-MAP激酶通路的激活。结果，A375细胞获得了OSM抗性表型。我们的研究结果表明，SOCS-3是OSM反应的有效调节因子，并提示SOCS-3表达失调可能为肿瘤进展过程中获得OSM抗性提供一种机制。
