This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kono, M. Articles by Kurnick, J. T. Search for Related Content PubMed PubMed Citation Articles by Kono, M. Articles by Kurnick, J. T.

---

Signaling and Regulation

Role of the Mitogen-Activated Protein Kinase Signaling Pathway in the Regulation of Human Melanocytic Antigen Expression

¹ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; ² Department of Dermatology, Nagoya University Graduate School of Medicine, Tsurumai, Showa-ku, Nagoya, Japan; ³ CytoCure LLC, Beverly, Massachusetts; and ⁴ Department of Immunopathology, Westmead Hospital, Sydney, New South Wales, Australia

Requests for reprints: James T. Kurnick, CytoCure LLC, 100 Cummings Center, Suite 430, Beverly, MA 01915. Phone: 978-232-1243; Fax: 978-232-1243. E-mail: kurnick{at}massmed.org

Heterogeneous expression of melanocytic antigens occurs frequently in melanomas and represents a potent barrier to immunotherapy. We previously showed that coordinated losses of several melanocytic antigens are generally attributable to down-regulation of antigen gene expression rather than irreversible mutation. Treatment of melanoma cells with mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors blocks ERK activation and increases steady-state levels of mRNAs and corresponding protein expression for the melanocytic antigens Melan-A/MART-1, gp100, and tyrosinase. Although the degree of MEK inhibitor enhancement of antigen expression varied among different cell lines irrespective of their antigen expression status, all showed detectable responses. Notably, the antigen-enhancing effects of the MEK inhibitors could not be attributed to the master melanocytic regulator MITF-M. Because MAPK pathway activation via constitutively active mutant forms of BRAF is common in melanomas, correlation between BRAF function and antigen expression was investigated. No simple correlation of endogenous BRAF mutational status and antigen levels was observed, but transient overexpression of V600E BRAF increased ERK activation and reduced Melan-A/MART-1 levels in antigen-positive cell lines. These data indicate that whereas multiple factors may regulate antigen expression in melanomas, enhancement of MAPK signaling can act as a negative influence. Blocking such signaling with MEK inhibitors accordingly augments antigen levels, thereby enhancing Melan-A/MART-1–specific cytotoxic T-cell responses to antigen-negative cells following MEK inhibition treatment. Consequently, MAPK inhibition may assist targeting of melanomas for immunotherapy. (Mol Cancer Res 2006;4(10):779–92)

This article has been cited by other articles:

				N. K. Haass, K. Sproesser, T. K. Nguyen, R. Contractor, C. A. Medina, K. L. Nathanson, M. Herlyn, and K. S.M. Smalley The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor AZD6244 (ARRY-142886) Induces Growth Arrest in Melanoma Cells and Tumor Regression When Combined with Docetaxel Clin. Cancer Res., January 1, 2008; 14(1): 230 - 239. [Abstract] [Full Text] [PDF]

				I. S. Dunn, T. J. Haggerty, M. Kono, P. J. Durda, D. Butera, D. B. Macdonald, E. M. Benson, L. B. Rose, and J. T. Kurnick Enhancement of Human Melanoma Antigen Expression by IFN-beta J. Immunol., August 15, 2007; 179(4): 2134 - 2142. [Abstract] [Full Text] [PDF]