TGF-?-induced growth inhibition in B-cell lymphoma correlates with Smad1/5 signalling and constitutively active p38 MAPK.

ABSTRACT:

Background

Cytokines of the transforming growth factor ? (TGF-?) superfamily exert effects on proliferation, apoptosis and differentiation in various cell types. Cancer cells frequently acquire resistance to the anti-proliferative signals of TGF-?, which can be due to mutations in proteins of the signalling cascade. We compared the TGF-?-related signalling properties in B-cell lymphoma cell lines that were sensitive or resistant to TGF-?-induced anti-proliferative effects.

Results

TGF-? sensitive cell lines expressed higher cell surface levels of the activin receptor-like kinase 5 (Alk-5), a TGF-? receptor type 1. The expression levels of the other TGF-? and bone morphogenetic protein receptors were comparable in the different cell lines. TGF-?-induced phosphorylation of Smad2 was similar in TGF-? sensitive and resistant cell lines. In contrast, activation of Smad1/5 was restricted to cells that were sensitive to growth inhibition by TGF-?. Moreover, with activin A we detected limited anti-proliferative effects, strong phosphorylation of Smad2, but no Smad1/5 phosphorylation. Up-regulation of the TGF-? target genes Id1 and Pai-1 was identified in the TGF-? sensitive cell lines. Constitutive phosphorylation of MAPK p38 was restricted to the TGF-? sensitive cell lines. Inhibition of p38 MAPK led to reduced sensitivity to TGF-?.

Conclusions

We suggest that phosphorylation of Smad1/5 is important for the anti-proliferative effects of TGF-? 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-?-induced anti-proliferative effects.

SUBMITTER: Bakkebo M 

PROVIDER: S-EPMC3006362 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature