Cell Growth & Differentiation, Vol 8, Issue 6 687-698, Copyright © 1997 by American Association of Cancer Research

ARTICLES

Retinoic acid induces signal transducer and activator of transcription (STAT) 1, STAT2, and p48 expression in myeloid leukemia cells and enhances their responsiveness to interferons

S Matikainen, T Ronni, A Lehtonen, T Sareneva, K Melen, S Nordling, DE Levy and I Julkunen
National Public Health Institute, Helsinki, Finland.

IFNs are antiproliferative cytokines that have growth-inhibitory effects on various normal and malignant cells. Therefore, they have been used in the treatment of certain forms of cancer, such as chronic myelogenous leukemia and hairy cell leukemia. However, there is little evidence that IFNs would be effective in the treatment of acute myelogenous leukemia, and molecular mechanisms underlying IFN unresponsiveness have not been clarified. Here we have studied the activation and induction of IFN-specific transcription factors signal transducer and activator of transcription (STAT) 1, STAT2, and p48 in all-trans-retinoic acid (ATRA)-differentiated myeloid leukemia cells using promyelocytic NB4, myeloblastic HL-60, and monoblastic U937 cells as model systems. These cells respond to ATRA by growth inhibition and differentiation. We show that in undifferentiated NB4 cells, 2',5'-oligoadenylate synthetase and MxB gene expression is not activated by IFN-alpha, possibly due to a relative lack of signaling molecules, especially p48 protein. However, during ATRA-induced differentiation, steady-state STAT1, STAT2, and especially p48 mRNA and corresponding protein levels were elevated both in NB4 and U937 cells, apparently correlating to an enhanced responsiveness of these cells to IFNs. ATRA treatment of NB4 cells sensitized them to IFN action as seen by increased IFN-gamma activation site DNA-binding activity or by efficient formation of IFN-alpha-specific ISGF3 complex and subsequent oligoadenylate synthetase and MxB gene expression. Lack of p48 expression could be one of the mechanisms of promyelocytic leukemia cell escape from growth-inhibitory effects of IFN-alpha.

This article has been cited by other articles:

				E. Parrella, M. Gianni', V. Cecconi, E. Nigro, M. M. Barzago, A. Rambaldi, C. Rochette-Egly, M. Terao, and E. Garattini Phosphodiesterase IV Inhibition by Piclamilast Potentiates the Cytodifferentiating Action of Retinoids in Myeloid Leukemia Cells: CROSS-TALK BETWEEN THE cAMP AND THE RETINOIC ACID SIGNALING PATHWAYS J. Biol. Chem., October 1, 2004; 279(40): 42026 - 42040. [Abstract] [Full Text] [PDF]

				L. Klampfer, J. Huang, G. Corner, J. Mariadason, D. Arango, T. Sasazuki, S. Shirasawa, and L. Augenlicht Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression J. Biol. Chem., November 21, 2003; 278(47): 46278 - 46287. [Abstract] [Full Text] [PDF]

				L. Yang, H. Zhao, S.-W. Li, K. Ahrens, C. Collins, S. Eckenrode, Q.-g. Ruan, R. A. McIndoe, and J.-X. She Gene Expression Profiling during All-trans Retinoic Acid-Induced Cell Differentiation of Acute Promyelocytic Leukemia Cells J. Mol. Diagn., November 1, 2003; 5(4): 212 - 221. [Abstract] [Full Text] [PDF]

				S. Kambhampati, Y. Li, A. Verma, A. Sassano, B. Majchrzak, D. K. Deb, S. Parmar, N. Giafis, D. V. Kalvakolanu, A. Rahman, et al. Activation of Protein Kinase C{delta} by All-trans-retinoic Acid J. Biol. Chem., August 29, 2003; 278(35): 32544 - 32551. [Abstract] [Full Text] [PDF]

				A. Dimberg, I. Karlberg, K. Nilsson, and F. Oberg Ser727/Tyr701-phosphorylated Stat1 is required for the regulation of c-Myc, cyclins, and p27Kip1 associated with ATRA-induced G0/G1 arrest of U-937 cells Blood, July 1, 2003; 102(1): 254 - 261. [Abstract] [Full Text] [PDF]

				M. Benekli, M. R. Baer, H. Baumann, and M. Wetzler Signal transducer and activator of transcription proteins in leukemias Blood, April 15, 2003; 101(8): 2940 - 2954. [Abstract] [Full Text] [PDF]

				F. Ravandi, M. Talpaz, and Z. Estrov Modulation of Cellular Signaling Pathways: Prospects for Targeted Therapy in Hematological Malignancies Clin. Cancer Res., February 1, 2003; 9(2): 535 - 550. [Abstract] [Full Text] [PDF]

				D. J. Lindner, X. Ma, J. Hu, S. Karra, and D. V. Kalvakolanu Thioredoxin Reductase Plays a Critical Role in IFN Retinoid-mediated Tumor-Growth Control in Vivo Clin. Cancer Res., October 1, 2002; 8(10): 3210 - 3218. [Abstract] [Full Text] [PDF]

				K. E. Luker, C. M. Pica, R. D. Schreiber, and D. Piwnica-Worms Overexpression of IRF9 Confers Resistance to Antimicrotubule Agents in Breast Cancer Cells Cancer Res., September 1, 2001; 61(17): 6540 - 6547. [Abstract] [Full Text] [PDF]

				A. Dimberg, K. Nilsson, and F. Oberg Phosphorylation-deficient Stat1 inhibits retinoic acid-induced differentiation and cell cycle arrest in U-937 monoblasts Blood, October 15, 2000; 96(8): 2870 - 2878. [Abstract] [Full Text] [PDF]

				M. Weiden, N. Tanaka, Y. Qiao, B. Y. Zhao, Y. Honda, K. Nakata, A. Canova, D. E. Levy, W. N. Rom, and R. Pine Differentiation of Monocytes to Macrophages Switches the Mycobacterium tuberculosis Effect on HIV-1 Replication from Stimulation to Inhibition: Modulation of Interferon Response and CCAAT/Enhancer Binding Protein {beta} Expression J. Immunol., August 15, 2000; 165(4): 2028 - 2039. [Abstract] [Full Text] [PDF]

				Y.-H. Chen, D. Lavelle, J. DeSimone, S. Uddin, L. C. Platanias, and M. Hankewych Growth Inhibition of a Human Myeloma Cell Line by All-trans Retinoic Acid Is Not Mediated Through Downregulation of Interleukin-6 Receptors but Through Upregulation of p21WAF1 Blood, July 1, 1999; 94(1): 251 - 259. [Abstract] [Full Text] [PDF]

				Y. Shang, C. R. Baumrucker, and M. H. Green c-Myc Is a Major Mediator of the Synergistic Growth Inhibitory Effects of Retinoic Acid and Interferon in Breast Cancer Cells J. Biol. Chem., November 13, 1998; 273(46): 30608 - 30613. [Abstract] [Full Text] [PDF]

				L. H. Wong, I. Hatzinisiriou, R. J. Devenish, and S. J. Ralph IFN-{gamma} Priming Up-Regulates IFN-Stimulated Gene Factor 3 (ISGF3) Components, Augmenting Responsiveness of IFN-Resistant Melanoma Cells to Type I IFNs J. Immunol., June 1, 1998; 160(11): 5475 - 5484. [Abstract] [Full Text] [PDF]

				J. E. Angell, D. J. Lindner, P. S. Shapiro, E. R. Hofmann, and D. V. Kalvakolanu Identification of GRIM-19, a Novel Cell Death-regulatory Gene Induced by the Interferon-beta and Retinoic Acid Combination, Using a Genetic Approach J. Biol. Chem., October 20, 2000; 275(43): 33416 - 33426. [Abstract] [Full Text] [PDF]

				Y. Alsayed, S. Uddin, N. Mahmud, F. Lekmine, D. V. Kalvakolanu, S. Minucci, G. Bokoch, and L. C. Platanias Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to All-trans-retinoic Acid J. Biol. Chem., February 2, 2001; 276(6): 4012 - 4019. [Abstract] [Full Text] [PDF]

				J.-B. Yang, Z.-J. Duan, W. Yao, O. Lee, L. Yang, X.-Y. Yang, X. Sun, C. C. Y. Chang, T.-Y. Chang, and B.-L. Li Synergistic Transcriptional Activation of Human Acyl-coenzyme A: Cholesterol Acyltransterase-1 Gene by Interferon-gamma and All-trans-Retinoic Acid THP-1 Cells J. Biol. Chem., June 8, 2001; 276(24): 20989 - 20998. [Abstract] [Full Text] [PDF]

				X. Ma, S. Karra, W. Guo, D. J. Lindner, J. Hu, J. E. Angell, E. R. Hofmann, S. P. M. Reddy, and D. V. Kalvakolanu Regulation of Interferon and Retinoic Acid-induced Cell Death Activation through Thioredoxin Reductase J. Biol. Chem., June 29, 2001; 276(27): 24843 - 24854. [Abstract] [Full Text] [PDF]