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(Journal of Leukocyte Biology. 2002;71:9-15.)
© 2002 by Society for Leukocyte Biology

Molecular mechanisms of glucocorticoid antiproliferative effects: antagonism of transcription factor activity by glucocorticoid receptor

Wassim Y. Almawi^* and Ohannes K. Melemedjian

^* Department of Medical Biochemistry, Arabian Gulf University, Manama, Bahrain; and
Department of Biology, American University of Beirut, Lebanon

Correspondence: Dr. Wassim Y. Almawi, Department of Medical Biochemistry, College of Medicine & Medical Sciences, Arabian Gulf University, P.O. Box 22979, Manama, Bahrain. E-mail: wassim{at}agu.edu.bh

Glucocorticoids (GCs) exert their anti-inflammatory and immunosuppressive effects by inhibiting the expression of cytokines and adhesion molecules. The molecular basis of GC action lies in their capacity to diffuse through the cell membrane and bind their cytosolic GC receptor (GR), which subsequently undergoes nuclear translocation and modulates transcriptional activation through association with promoter elements, GC response elements (GRE). GR also antagonized the activity of transcription factors, including NF-B, NF-AT, and AP-1, through direct and indirect mechanisms. GCs induced the gene transcription and protein synthesis of the NF-B inhibitor, IB. Activated GR antagonized transcription factor activity through protein:protein interaction. This involved complexing with and inhibition of transcription factor binding to DNA (simple model), association with factor bound at its DNA site (composite model), and/or through interaction of GRE-bound GR with DNA-bound transcription factor (transmodulation model). Finally, GR competed with transcription factors for nuclear coactivators (competition model), including CBP and p300. Remarkably, GR did not affect the assembly of the preinitiation complex but acted proximally in inhibiting transcription factor activity and thus transcriptional initiation.

Key Words: GRE • NF-B • NF-AT • AP-1 • transactivation • transrepression

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