Soluble adenylyl cyclase (sAC) is a unique class of adenylyl cyclase, the enzyme responsible for generation of cAMP. cAMP is a key intracellular signaling molecule involved in regulation of melanocyte differentiation, proliferation and melanogenesis. sAC is ubiquitously expressed in many tissues1-3 and is localized in different subcellular microdomains (cytoplasm, Golgi area, nucleus). sAC generated cAMP in response to both extracellular (TNF, Netrin, NGF) or intracellular (bicarbonate, pH, calcium) signals.(2, 4-12)
Magro et al. have recently reported expression of sAC in benign melanocytic proliferations and melanomas using a monoclonal antibody against sAC designated R21. (13) They showed that using R21 immunohistochemistry in benign nevi sAC is expressed predominantly in perinuclear Golgi region. In contrast, different histological subsets of melanoma show distinct predominant patterns and intensity of staining with R21. The most striking reproducible pattern is strong pan-nuclear expression of sAC in lentigo maligna melanoma.
Working in collaboration with Dr. Magro and her colleagues at Cornell, we optimized immunohistochemical protol of staining with R21 for differential diagnosis between lentigo maligna, junctional nevus and lentiginous melanocytic hyperplasia. Under our conditions, 90% of lentigo malignas show nuclear expression of sAC. In contrast, nuclear expression almost never detected in nevi (including atypical dysplastic nevi). However, a subtantial percentage (25-30%) of lentiginous melanocytic hyperplasias associated with lentigo can show focal nuclear staining. (Our paper is in press in Archives of Pathology and Laboratory Medicine)
In this project, we posted recent cases in which we used R21 immunohistochemistry to show how we interpret R21 staining in our routine practice. Please note that login is required to read a comment about each case.
R21 can be purchased from CEP Biotech.
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(3) Zippin JH, Chadwick PA, Levin LR, Buck J, Magro CM. Soluble adenylyl cyclase defines a nuclear cAMP microdomain in keratinocyte hyperproliferative skin diseases. J Invest Dermatol 2010 May;130(5):1279-1287.
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(10) Hess KC, Jones BH, Marquez B et al. The "soluble" adenylyl cyclase in sperm mediates multiple signaling events required for fertilization. Dev Cell 2005 August;9(2):249-259.
(11) Zippin JH, Chen Y, Nahirney P et al. Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct signaling microdomains. FASEB J 2003 January;17(1):82-84.
(12) Zippin JH, Farrell J, Huron D et al. Bicarbonate-responsive "soluble" adenylyl cyclase defines a nuclear cAMP microdomain. J Cell Biol 2004 February 16;164(4):527-534.
(13) Magro CM, Crowson AN, Desmaze C, Zippin JH. The sAC Antibody Profile as a Diagnostic Adjunct in the Assessment of Pigmented Lesions. Arch Dermatol. In press 2011.