Cell Growth & Differentiation, Vol 8, Issue 2 213-219, Copyright © 1997 by American Association of Cancer Research

ARTICLES

Involvement of the transcription factor NF-IL6 in phorbol ester induction of P-glycoprotein in U937 cells

NJ Combates, PO Kwon, RW Rzepka and D Cohen
Oncology Research Program, Sandoz Research Institute, East Hanover, New Jersey 07936, USA.

Previously, we showed that the nuclear factor NF-IL6 binds and trans-activates the promoter of the human multidrug resistance gene (MDR1) encoding P-glycoprotein (N. J. Combates et al., J. Biol. Chem., 269: 29715-29719, 1994). In this study, we investigated the physiological relevance of MDR1 gene regulation by NF-IL6 in response to PMA (phorbol 12-myristate 13-acetate)-induced differentiation. Treatment of U937 cells, a human promonocytic cell line, with PMA induced their differentiation along the macrophage/monocytic cell lineage. The cellular changes were found to be accompanied by an increase in P-glycoprotein expression at the cell surface. PMA treatment of U937 cells also resulted in the synthesis of the three forms of NF-IL6 and an enhanced DNA binding activity of nuclear extracts to a probe derived from the MDR1 promoter. The majority of the DNA-protein complex could be supershifted by an NF-IL6 reactive antibody but not by antibodies for CAAT/enhancer binding protein alpha and delta, c-fos, or c-jun. Furthermore, transient transfection studies demonstrated that PMA enhanced the activity of a MDR1 promoter-driven luciferase gene construct to a greater extent as compared with the activity of a reporter construct containing mutations within the NF-IL6 responsive element. These results indicate a correlation between NF-IL6 gene expression and the regulation of the MDR1 gene. Furthermore, these observations also suggest that P-glycoprotein expression is part of the macrophage differentiation process.

This article has been cited by other articles:

				L. Mickley Huff, Z. Wang, A. Iglesias, T. Fojo, and J.-S. Lee Aberrant Transcription from an Unrelated Promoter Can Result in MDR-1 Expression following Drug Selection In vitro and in Relapsed Lymphoma Samples Cancer Res., December 15, 2005; 65(24): 11694 - 11703. [Abstract] [Full Text] [PDF]

				M. Kuwano, Y. Oda, H. Izumi, S.-J. Yang, T. Uchiumi, Y. Iwamoto, M. Toi, T. Fujii, H. Yamana, H. Kinoshita, et al. The role of nuclear Y-box binding protein 1 as a global marker in drug resistance Mol. Cancer Ther., November 1, 2004; 3(11): 1485 - 1492. [Abstract] [Full Text] [PDF]

				K. M. Comerford, T. J. Wallace, J. Karhausen, N. A. Louis, M. C. Montalto, and S. P. Colgan Hypoxia-inducible Factor-1-dependent Regulation of the Multidrug Resistance (MDR1) Gene Cancer Res., June 1, 2002; 62(12): 3387 - 3394. [Abstract] [Full Text] [PDF]

				D. Conze, L. Weiss, P. S. Regen, A. Bhushan, D. Weaver, P. Johnson, and M. Rincon Autocrine Production of Interleukin 6 Causes Multidrug Resistance in Breast Cancer Cells Cancer Res., December 1, 2001; 61(24): 8851 - 8858. [Abstract] [Full Text] [PDF]

				J.-M. Yang, A. D. Vassil, and W. N. Hait Activation of Phospholipase C Induces the Expression of the Multidrug Resistance (MDR1) Gene through the Raf-MAPK Pathway Mol. Pharmacol., October 1, 2001; 60(4): 674 - 680. [Abstract] [Full Text] [PDF]

				K. W. Scotto and R. A. Johnson Transcription of MDR1: A Therapeutic Target Mol. Interv., June 1, 2001; 1(2): 117 - 125. [Abstract] [Full Text] [PDF]

				V. K. Harris, E. D. E. Liaudet-Coopman, B. J. Boyle, A. Wellstein, and A. T. Riegel Phorbol Ester-induced Transcription of a Fibroblast Growth Factor-binding Protein Is Modulated by a Complex Interplay of Positive and Negative Regulatory Promoter Elements J. Biol. Chem., July 24, 1998; 273(30): 19130 - 19139. [Abstract] [Full Text] [PDF]

				T. Ohga, T. Uchiumi, Y. Makino, K. Koike, M. Wada, M. Kuwano, and K. Kohno Direct Involvement of the Y-box Binding Protein YB-1 in Genotoxic Stress-induced Activation of the Human Multidrug Resistance 1 Gene J. Biol. Chem., March 13, 1998; 273(11): 5997 - 6000. [Abstract] [Full Text] [PDF]