Abstract
BackgroundCytokines 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.ResultsTGF-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.ConclusionsWe 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.
Highlights
Cytokines of the transforming growth factor b (TGF-b) superfamily exert effects on proliferation, apoptosis and differentiation in various cell types
The members of the TGF-b superfamily of cytokines, which consists of TGF-bs, bone morphogenetic proteins (BMPs) and activins, exert potent effects on proliferation, apoptosis and differentiation on many different cell types, including primary B cells [1,2]
B-cell lymphoma show reduced sensitivity to TGF-b compared to primary B cells Many cancer types develop resistance to TGF-b-induced growth inhibition
Summary
Cytokines of the transforming growth factor b (TGF-b) superfamily exert effects on proliferation, apoptosis and differentiation in various cell types. We compared the TGF-brelated signalling properties in B-cell lymphoma cell lines that were sensitive or resistant to TGF-b-induced antiproliferative effects. The members of the TGF-b superfamily of cytokines, which consists of TGF-bs, bone morphogenetic proteins (BMPs) and activins, exert potent effects on proliferation, apoptosis and differentiation on many different cell types, including primary B cells [1,2]. The signalling is initiated through heterotetrameric complexes of type I and type II receptors. The cytokines bind to a type II receptor, and type I is recruited and activated through phosphorylation. There are five type II and seven type I receptors which form complexes with the TGF-b superfamily of cytokines. It is suggested that this regulation often occurs through phosphorylation of the linker region of R-Smads, which can be activating or inhibitory to the effects of TGF-bs, activins or BMPs
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