Reference : Interferon-gamma-mediated growth regulation of melanoma cells: involvement of STAT1-d...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Interferon-gamma-mediated growth regulation of melanoma cells: involvement of STAT1-dependent and STAT1-independent signals
Kortylewski, M. [> >]
Komyod, W. [> >]
Kauffmann, M. E. [> >]
Bosserhoff, A. K. [> >]
Heinrich, P. C. [> >]
Behrmann, Iris mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Journal of Investigative Dermatology
Nature Publishing Group
Yes (verified by ORBilu)
New York
[en] 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
[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.

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