Genomic and non-genomic intracelular pathways envolved in thyroid hormone mediated T lymphoma cell proliferation

CREMASCHI G.A.; FARÍAS R.N.; KLECHA A.J.; STERLE H.A.; GENARO A.M.; BARREIRO ARCOS M.L.

Creta, Grecia

Workshop; 5 th International Leukocyte Signal Transduction Workshop; 2009

AEGEAN CONFERENCES

 Thyroid hormones (THs) exert a broad range of actions on development, growth and cell differentiation by both genomic and non-genomic mechanisms. We have previosly shown that THs induce Bw 5147 T lymphoma (BW) cell division, through the activation of the atypical protein kinase z (PKC z) and dthe inducible isoform of nitric oxide synthase (iNOS). The aim of this work was to analyze the contribution of both genomic and non-genomic effects in this intracellular signals.For this purpose the action of non-cell permeable THs coupled to agarose (TH-ag) was analyzed. Both T3-ag and T4-ag induced BW cell proliferation, although to a lesser extent than free hormones. THs as well as TH-ag induced the rapid translocation of PKC to cell membranes, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and the activation of NF-kB. THs but not TH-ag lead to NOS activation and to an increase in iNOS expression both at the protein and mRNA levels. Selective blockers of acidic and neutral sphingomielinases, imipramine and GW 4869 respectively, inhibited THs and TH-ag effects on proliferation and on PKCz activity. Also pretreatment of T lymphoma cells with the myristoylated PKCz pseudosubstrate inhibited the same actions, NF-kB and the TH-mediated activation od NOS activity as well.These results indicate that THs trigger a non-genomic signaling cascade that involves sphingomielinases-mediated activation of PKCz. As a consequence of this ERK1/2 and NF-kB are activated down-stream PKCz, leading in this way to the genomic increase of iNOS and to cell proliferation