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Article (Scientific journals)
Interferon-gamma-mediated growth regulation of melanoma cells: involvement of STAT1-dependent and STAT1-independent signals
Kortylewski, M.; Komyod, W.; Kauffmann, M. E. et al.
2004In Journal of Investigative Dermatology, 122 (2), p. 414-22
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Keywords :
Antineoplastic Agents; Skin Neoplasms; Signal Transduction; STAT1 Transcription Factor; Melanoma; Interferon Type II; Humans; Gene Expression Regulation, Neoplastic; G1 Phase; G0 Phase; Drug Resistance, Neoplasm; Down-Regulation; DNA-Binding Proteins; Cyclins; Cyclin-Dependent Kinases; Cell Line, Tumor; Trans-Activators
Abstract :
[en] Interferon-gamma, a known inhibitor of tumor cell growth, has been used in several protocols for the treatment of melanoma. We have studied the molecular events underlying interferon-gamma-induced G0/G1 arrest in four metastatic melanoma cell lines with different responsiveness to interferon-gamma. The growth arrest did not result from enhanced expression of cyclin-dependent kinase inhibitors p21 and p27. Instead, it correlated with downregulation of cyclin E and cyclin A and inhibition of their associated kinase activities. We show that interferon-gamma-induced growth inhibition could be abrogated by overexpression of dominant negative STAT1 (signal transducer and activator of transcription 1) in the melanoma cell line A375, suggesting that STAT1 plays a crucial part for the anti-proliferative effect. Erythropoietin stimulation of a chimeric receptor led to a concentration-dependent STAT1 activation and concomitant growth arrest when it contained the STAT recruitment motif Y440 of the interferon-gamma receptor 1. In contrast, dose-response studies for interferon-gamma revealed a discrepancy between levels of STAT1 activation and the extent of growth inhibition; whereas STAT1 was activated by low doses of interferon-gamma (10 U per mL), growth inhibitory effects were only visible with 100-fold higher concentrations. Our results suggest the presence of additional signals emanating from the interferon-gamma receptor, which may counteract the anti-proliferative function of STAT1.
Disciplines :
Biochemistry, biophysics & molecular biology
Identifiers :
Author, co-author :
Kortylewski, M.
Komyod, W.
Kauffmann, M. E.
Bosserhoff, A. K.
Heinrich, P. C.
Behrmann, Iris ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
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Title :
Interferon-gamma-mediated growth regulation of melanoma cells: involvement of STAT1-dependent and STAT1-independent signals
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Journal title :
Journal of Investigative Dermatology
Publisher :
Nature Publishing Group, New York, United States - New York
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Issue :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
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