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Integrin Signaling to NF-B in Monocytic Leukemia Cells Is Blocked by Activated Oncogenes¹

Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Integrin-mediated signals play an important but poorly understood role in regulating the growth and behavior of tumor cells. In monocytes and monocytic leukemia cells, integrin-mediated adhesion results in a strong induction of a set of immediate early genes that are characteristic of monocytic differentiation and contain consensus NF-B elements in their 5' regulatory regions. To investigate the role of integrin signaling in control of differentiation in a human monocytic leukemia cell line, THP-1 cells were transiently transfected with an NF-B driven CAT reporter gene. Adhesion to fibronectin or cross-linking of ß1 integrins resulted in an NF-B-dependent induction of CAT activity. To evaluate whether integrin signaling in this system intersects with the Ras signal transduction cascade, THP-1 cells were cotransfected with the NF-B reporter and with plasmids that direct the synthesis of normal or mutant forms of Ras or Raf. We found that Ras or Raf dominant negative mutants did not inhibit integrin-mediated activation of the NF-B-driven reporter. However, cotransfection with activated Ras, or with several other cytoplasmic oncogenes, blocked this process. This suggests that in monocytic leukemia cells, an antagonism 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.

¹ This work was supported by NIH Grants GM26165 and NHLBI 45100 to R. L. J.

² Present address: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de Mexico, Apto. Postal 70228, Ciudad Universitaria, México, D.F.-04510, Mexico.

³ To whom requests for reprints should be addressed, at Department of Pharmacology, School of Medicine, University of North Carolina, CB #7365, Faculty Laboratory Office Building, Chapel Hill, NC 27599-7365.

Received 3/18/96. Accepted 4/ 2/96.

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