Department of Immunology, Institute for Cancer Research, Oslo University Hospital Montebello, Oslo, Norway.
BMC Immunol. 2010 Nov 23;11:57. doi: 10.1186/1471-2172-11-57.
Cytokines of the transforming growth factor β (TGF-β) superfamily exert effects on proliferation, apoptosis and differentiation in various cell types. Cancer cells frequently acquire resistance to the anti-proliferative signals of TGF-β, which can be due to mutations in proteins of the signalling cascade. We compared the TGF-β-related signalling properties in B-cell lymphoma cell lines that were sensitive or resistant to TGF-β-induced anti-proliferative effects.
TGF-β sensitive cell lines expressed higher cell surface levels of the activin receptor-like kinase 5 (Alk-5), a TGF-β receptor type 1. The expression levels of the other TGF-β and bone morphogenetic protein receptors were comparable in the different cell lines. TGF-β-induced phosphorylation of Smad2 was similar in TGF-β sensitive and resistant cell lines. In contrast, activation of Smad1/5 was restricted to cells that were sensitive to growth inhibition by TGF-β. Moreover, with activin A we detected limited anti-proliferative effects, strong phosphorylation of Smad2, but no Smad1/5 phosphorylation. Up-regulation of the TGF-β target genes Id1 and Pai-1 was identified in the TGF-β sensitive cell lines. Constitutive phosphorylation of MAPK p38 was restricted to the TGF-β sensitive cell lines. Inhibition of p38 MAPK led to reduced sensitivity to TGF-β.
We suggest that phosphorylation of Smad1/5 is important for the anti-proliferative effects of TGF-β in B-cell lymphoma. Alk-5 was highly expressed in the sensitive cell lines, and might be important for signalling through Smad1/5. Our results indicate a role for p38 MAPK in the regulation of TGF-β-induced anti-proliferative effects.
转化生长因子 β（TGF-β）超家族的细胞因子对各种细胞类型的增殖、凋亡和分化有影响。癌细胞经常对 TGF-β的抗增殖信号产生抗性，这可能是由于信号转导级联中的蛋白质发生突变。我们比较了对 TGF-β诱导的抗增殖作用敏感和耐药的 B 细胞淋巴瘤细胞系中的 TGF-β相关信号特性。
TGF-β 敏感细胞系表达更高的细胞表面激活素受体样激酶 5（Alk-5）水平，这是一种 TGF-β 受体 1。不同细胞系中 TGF-β 和骨形态发生蛋白受体的表达水平相当。TGF-β 诱导的 Smad2 磷酸化在 TGF-β 敏感和耐药细胞系中相似。相反，Smad1/5 的激活仅限于对 TGF-β 抑制生长敏感的细胞。此外，我们用激活素 A 检测到有限的抗增殖作用，强烈的 Smad2 磷酸化，但没有 Smad1/5 磷酸化。在 TGF-β 敏感细胞系中鉴定到 TGF-β 靶基因 Id1 和 Pai-1 的上调。MAPK p38 的组成性磷酸化仅限于 TGF-β 敏感细胞系。抑制 p38 MAPK 导致对 TGF-β 的敏感性降低。
我们认为 Smad1/5 的磷酸化对于 TGF-β 在 B 细胞淋巴瘤中的抗增殖作用很重要。Alk-5 在敏感细胞系中高表达，可能对 Smad1/5 的信号转导很重要。我们的结果表明 p38 MAPK 在调节 TGF-β 诱导的抗增殖作用中起作用。
