التفاصيل البيبلوغرافية
| العنوان: |
Dual c-Jun N-terminal kinase-cyclin D1 and extracellular signal-related kinase-c-Jun disjunction in human melanoma. |
| المؤلفون: |
Pathria, G., Garg, B., Garg, K., Wagner, C., Wagner, S.N. |
| المصدر: |
British Journal of Dermatology; Dec2016, Vol. 175 Issue 6, p1221-1231, 11p |
| مصطلحات موضوعية: |
MELANOMA, CYCLINS, SKIN cancer, GROWTH factors, MESSENGER RNA |
| مستخلص: |
Background Activity of both c-Jun and cyclin D1 is deemed critical for melanoma cell proliferation. This functionality is corroborated by frequently elevated expression and activity of these proteins in human melanomas. Correspondingly, alleviating c-Jun and cyclin D1 function is vital to the success of antimelanoma therapeutics. Objectives To understand the role of the c-Jun N-terminal kinase ( JNK) signalling pathway in melanoma cell proliferation and survival. Methods The effect of JNK inhibitors SP600125 and JNK- IN-8 on the proliferation and survival of genetically highly representative human melanoma cell lines was studied in assays of proliferation and apoptosis. Changes in c-Jun and cyclin D1 protein and mRNA levels in response to JNK and mitogen-activated protein kinase kinase ( MEK) inhibition were investigated through immunoblotting and quantitative reverse-transcription polymerase chain reaction. The effects of JNK and MEK inhibitors on cell-cycle distribution were assessed by flow cytometry. Results We demonstrate the requirement of JNK signalling in melanoma cell proliferation and survival. While JNK inhibition suppressed the expression and activity of c-Jun, it failed to suppress cyclin D1 levels. Consistently with its inability to downregulate cyclin D1, JNK inhibition failed to induce G1 arrest. In contrast, the blockade of MEK-extracellular signal-regulated kinase ( ERK) signalling, although unable to suppress c-Jun activity and expression, paradoxically abated cyclin D1 levels and triggered G1 arrest. This previously unreported dual disconnect between JNK-cyclin D1 and ERK-c-Jun levels was confirmed by concomitant JNK and BRAF inhibition, which suppressed both c-Jun and cyclin D1 levels and exhibited a heightened antiproliferative response. Conclusions Dual disjunction between JNK-cyclin D1 and ERK-c-Jun signalling forms the basis for further investigation of combined JNK and MAPK signalling blockade as a more effective therapeutic approach in human melanoma. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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