Overexpression of protein kinase C-ζ (PKC-ζ) in the leukemic myeloid cell line U937 (U937-PKC-ζ cells), previously shown to induce leukemic cell differentiation, resulted in nearly complete downregulation of leukocyte integrins CD11a, CD11b, CD11d, and CD18, but not CD11c from the cell surface. The steady-state level of mRNAs for the downregulated leukocyte integrins was not detectable by Northern analysis. Nuclear run-on analysis revealed that transcription of all the leukocyte integrin genes except CD11c was reduced 70-90% as compared to control U937-Vector cells [U937 cells transfected with the empty vector pSV2M(2)6]. Transfection analysis of CD11-promoter-luciferase constructs confirmed that transcription of the leukocyte integrin genes was drastically downregulated in U937-PKC-ζ cells. The two c-jun binding sites in the CD11c promoter were essential for continued expression of CD11c in U937-PKC-ζ cells. Additionally, the 3' untranslated region (3' UTR) from CD11b, when fused to the luciferase gene, lead to the destabilization of this chimeric mRNA in U937-PKC-ζ cells. This indicates that downregulation of CD11b expression in U937-PKC-ζ cells is also the result of reduced stability of CD11b mRNA. Thus, overexpression of PKC-ζ in U937 cells leads not only to leukemic cell differentiation, but also to differential regulation of the leukocyte integrins.

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