ACTIVATION OF THE JAK2-STAT5 SIGNALING PATHWAY IN NB2 LYMPHOMA-CELLS BY AN ANTI-APOPTOTIC AGENT, AURINTRICARBOXYLIC ACID

Biological effects of many hormones and cytokines are mediated through receptor-associated Jak tyrosine kinases and cytoplasmic Stat transcr iption factors, including critical physiological processes such as imm unity, reproduction, and cell growth and differentiation. Pharmaceutic als that control Jak-Stat pathways are therefore of considerable inter est. Here we demonstrate that a single Jak-Stat pathway can be activat ed by aurintricarboxylic acid (ATA), a negatively charged triphenylmet hane derivative (475 Da) with anti-apoptotic properties, In prolactin (PRL)-dependent Nb2 lymphocytes, ATA sustained cell growth in the abse nce of hormone and mimicked rapid PRL-induced tyrosine phosphorylation of Jak2 and activation of Stat5a and Stat5b with tyrosine phosphoryla tion, heterodimerization, DNA binding, and induction of the Stat5-regu lated pim-1 protooncogene. ATA also mimicked PRL activation of serine kinases ERK1 and ERK2, However, unlike PRL, ATA did not regulate Stat1 or Stat3, ATA also did not affect Jak8, which is activated in these c ells by interleukin-a family cytokines, Although the mechanism and spe cificity by which ATA activates Jak2, Stat5, and ERKs in Nb2 cells are still unclear, the present study demonstrates that certain hormone or cytokine effects on Jak-Stat pathways can be discretely imitated by a low molecular weight, non-peptide pharmaceutical. The results are als o consistent with Stat5 involvement in lymphocyte growth and survival.