Elucidation of Mechanisms Underlying Metastatic Melanoma Immune Escape via Suppression of Major Histocompatibility Complex (MHC) II through Dysregulation of the JAK/STAT Pathway
Transcriptional activation of Major Histocompatability Complex (MHC) I and II molecules by the cytokine interferon gamma (IFN-g) is a key step in cell-mediated immunity against pathogens and tumors. Following IFN-g induction, JAK/STAT signaling triggers activation of MHC genes. Recent evidence sugge...
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ndltd-GEORGIA-oai-scholarworks.gsu.edu-biology_diss-11602015-05-05T15:37:40Z Elucidation of Mechanisms Underlying Metastatic Melanoma Immune Escape via Suppression of Major Histocompatibility Complex (MHC) II through Dysregulation of the JAK/STAT Pathway Osborn, Jodi Transcriptional activation of Major Histocompatability Complex (MHC) I and II molecules by the cytokine interferon gamma (IFN-g) is a key step in cell-mediated immunity against pathogens and tumors. Following IFN-g induction, JAK/STAT signaling triggers activation of MHC genes. Recent evidence suggests suppression of MHC I and II expression on multiple tumor types plays important roles in tumor immunoevasion. One such tumor is malignant melanoma, the leading cause of skin cancer related deaths. Despite awareness of MHC expression defects, the molecular mechanisms by which melanoma cells suppress MHC and escape from immune-mediated destruction remain unknown. Here we analyze dysregulation of the JAK/STAT pathway and its role in suppression of MHC II in melanoma cell lines at the Radial Growth Phase (RGP), the Vertical Growth Phase (VGP) and the Metastatic Phase (MET). RGP and VGP cells express both MHC II and the MHC master regulator, the Class II Transactivator (CIITA). MET cells lack not only MHC II and CIITA, but also both STAT 1 and the STAT 1 coactivator, the Interferon Response Factor (IRF) 1. Our studies have implicated that the suppression of MHCII on the cell surface of metastatic melanoma is due to silencing at the level of STAT1 transcription. Furthermore, we determined that silencing of STAT1 is, in part, due to hemi-methylation of the STAT1 promoter. 2015-05-11T07:00:00Z text application/pdf http://scholarworks.gsu.edu/biology_diss/155 http://scholarworks.gsu.edu/cgi/viewcontent.cgi?article=1160&context=biology_diss Biology Dissertations ScholarWorks @ Georgia State University melanoma STAT1 MHC II immunosurveillance |
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melanoma STAT1 MHC II immunosurveillance Osborn, Jodi Elucidation of Mechanisms Underlying Metastatic Melanoma Immune Escape via Suppression of Major Histocompatibility Complex (MHC) II through Dysregulation of the JAK/STAT Pathway |
description |
Transcriptional activation of Major Histocompatability Complex (MHC) I and II molecules by the cytokine interferon gamma (IFN-g) is a key step in cell-mediated immunity against pathogens and tumors. Following IFN-g induction, JAK/STAT signaling triggers activation of MHC genes. Recent evidence suggests suppression of MHC I and II expression on multiple tumor types plays important roles in tumor immunoevasion. One such tumor is malignant melanoma, the leading cause of skin cancer related deaths. Despite awareness of MHC expression defects, the molecular mechanisms by which melanoma cells suppress MHC and escape from immune-mediated destruction remain unknown. Here we analyze dysregulation of the JAK/STAT pathway and its role in suppression of MHC II in melanoma cell lines at the Radial Growth Phase (RGP), the Vertical Growth Phase (VGP) and the Metastatic Phase (MET). RGP and VGP cells express both MHC II and the MHC master regulator, the Class II Transactivator (CIITA). MET cells lack not only MHC II and CIITA, but also both STAT 1 and the STAT 1 coactivator, the Interferon Response Factor (IRF) 1. Our studies have implicated that the suppression of MHCII on the cell surface of metastatic melanoma is due to silencing at the level of STAT1 transcription. Furthermore, we determined that silencing of STAT1 is, in part, due to hemi-methylation of the STAT1 promoter. |
author |
Osborn, Jodi |
author_facet |
Osborn, Jodi |
author_sort |
Osborn, Jodi |
title |
Elucidation of Mechanisms Underlying Metastatic Melanoma Immune Escape via Suppression of Major Histocompatibility Complex (MHC) II through Dysregulation of the JAK/STAT Pathway |
title_short |
Elucidation of Mechanisms Underlying Metastatic Melanoma Immune Escape via Suppression of Major Histocompatibility Complex (MHC) II through Dysregulation of the JAK/STAT Pathway |
title_full |
Elucidation of Mechanisms Underlying Metastatic Melanoma Immune Escape via Suppression of Major Histocompatibility Complex (MHC) II through Dysregulation of the JAK/STAT Pathway |
title_fullStr |
Elucidation of Mechanisms Underlying Metastatic Melanoma Immune Escape via Suppression of Major Histocompatibility Complex (MHC) II through Dysregulation of the JAK/STAT Pathway |
title_full_unstemmed |
Elucidation of Mechanisms Underlying Metastatic Melanoma Immune Escape via Suppression of Major Histocompatibility Complex (MHC) II through Dysregulation of the JAK/STAT Pathway |
title_sort |
elucidation of mechanisms underlying metastatic melanoma immune escape via suppression of major histocompatibility complex (mhc) ii through dysregulation of the jak/stat pathway |
publisher |
ScholarWorks @ Georgia State University |
publishDate |
2015 |
url |
http://scholarworks.gsu.edu/biology_diss/155 http://scholarworks.gsu.edu/cgi/viewcontent.cgi?article=1160&context=biology_diss |
work_keys_str_mv |
AT osbornjodi elucidationofmechanismsunderlyingmetastaticmelanomaimmuneescapeviasuppressionofmajorhistocompatibilitycomplexmhciithroughdysregulationofthejakstatpathway |
_version_ |
1716802546705629184 |