INTEGRIN SIGNALING TO NF-KAPPA-B IN MONOCYTIC LEUKEMIA-CELLS IS BLOCKED BY ACTIVATED ONCOGENES

Integrin-mediated signals play an important but poorly understood role in regulating the growth and behavior of tumor cells, in monocytes an d monocytic leukemia cells, integrin-mediated adhesion results in a st rong induction of a set of immediate early genes that are characterist ic of monocytic differentiation and contain consensus NF-kappa B eleme nts in their 5' regulatory regions. To investigate the rob of integrin signaling in control of differentiation in a human monocytic leukemia cell line, THP-1 cells were transiently transfected with an NF-kappa B driven CAT reporter gene, Adhesion to fibronectin or cross-linking o f beta 1 integrins resulted in an NF-kappa B-dependent induction of CA T activity. To evaluate whether integrin signaling in this system inte rsects with the Ras signal transduction cascade, THP-1 cells were cotr ansfected with the NF-kappa B reporter and with plasmids that direct t he synthesis of normal or mutant forms of Ras or Raf. We found that Ra s or Raf dominant negative mutants did not inhibit integrin-mediated a ctivation of the NF-kappa B-driven reporter, However, cotransfection w ith activated Ras, or with several other cytoplasmic oncogenes, blocke d this process. This suggests that in monocytic leukemia cells, an ant agonism exists between the mitogenic signals provided by oncogenes and the signals generated by integrin ligation, This antagonism may play an important role in regulating the balance between proliferation and differentiation in monocytic leukemias.