Cytokine resistance in melanoma
type: CreativeWork
description: Cytokines play an important role in the growth regulation of melanoma cells. Whereas the growth of melanocytes and many early stage melanoma cells can be inhibited by cytokines, melanoma cells of advanced tumor stages have often been reported to be “multi-cytokine resistant”. Thus, the aim of this study was to investigate the molecular mechanisms underlying cytokine resistance of melanoma cells. Transcription factors of the STAT family are crucial in signal transduction of cytokines. Previously, it has been reported that methylation of STAT1 on a conserved arginine residue (Arg31) is important for STAT1 function and loss of this modification was proposed to be involved in interferon resistance of cancer cells. Since STAT3 is involved in growth inhibition of melanoma cells, in the first part of this thesis I thus investigated the arginine methylation of STAT3 and STAT1. Here I provide several independent lines of evidence that did not support the occurrence of arginine methylation of STAT1 or STAT3. First, it was shown that the anti-methylarginine antibodies did not precipitate specifically STAT1 or STAT3. Second, it was shown that the methylation inhibitors, MTA and MDA, had profound and rapid effects on phosphorylation of STAT1 and STAT3, but MDA additionally also affected the p38 and Erk signaling cascades which are known to cross-talk with the Jak/STAT pathway. Third, it was shown that mutation of Arg31 to Lys led to destabilization of STAT1 and STAT3, implicating an important structural role of Arg31. Finally, the in vitro methylation assay using purified catalytically active protein arginine methyltransferases (PRMT1, -2, -3, -4, and -6) demonstrated that STAT proteins are not methylated, and cotransfection of PRMT1 did not affect STAT1-controlled reporter gene activity. Taken together, the data presented in this thesis suggest the absence of arginine methylation of STAT1 and STAT3. The Jak/STAT signaling pathway is subject to feedback inhibition by members of …
abstract: Cytokines play an important role in the growth regulation of melanoma cells. Whereas the growth of melanocytes and many early stage melanoma cells can be inhibited by cytokines, melanoma cells of advanced tumor stages have often been reported to be “multi-cytokine resistant”. Thus, the aim of this study was to investigate the molecular mechanisms underlying cytokine resistance of melanoma cells. Transcription factors of the STAT family are crucial in signal transduction of cytokines. Previously, it has been reported that methylation of STAT1 on a conserved arginine residue (Arg31) is important for STAT1 function and loss of this modification was proposed to be involved in interferon resistance of cancer cells. Since STAT3 is involved in growth inhibition of melanoma cells, in the first part of this thesis I thus investigated the arginine methylation of STAT3 and STAT1. Here I provide several independent lines of evidence that did not support the occurrence of arginine methylation of STAT1 or STAT3. First, it was shown that the anti-methylarginine antibodies did not precipitate specifically STAT1 or STAT3. Second, it was shown that the methylation inhibitors, MTA and MDA, had profound and rapid effects on phosphorylation of STAT1 and STAT3, but MDA additionally also affected the p38 and Erk signaling cascades which are known to cross-talk with the Jak/STAT pathway. Third, it was shown that mutation of Arg31 to Lys led to destabilization of STAT1 and STAT3, implicating an important structural role of Arg31. Finally, the in vitro methylation assay using purified catalytically active protein arginine methyltransferases (PRMT1, -2, -3, -4, and -6) demonstrated that STAT proteins are not methylated, and cotransfection of PRMT1 did not affect STAT1-controlled reporter gene activity. Taken together, the data presented in this thesis suggest the absence of arginine methylation of STAT1 and STAT3. The Jak/STAT signaling pathway is subject to feedback inhibition by members of …
author: Komyod, Waraporn
language: eng
keywords: info:eu-repo/classification/ddc/610, Medizin, Zytokine, Melanom, Jak/STAT, SOCS3, Argininmethylierung, cytokine, melanoma, arginine methylation
date published: 2007
date modified: 2026-07-30T19:43:28Z
provider: RWTH Aachen University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Publikationsserver der RWTH Aachen University