Soluble adenylyl cyclase defines a nuclear cAMP microdomain in keratinocyte hyperproliferative skin diseases.
Cyclic adenosine monophosphate (cAMP) is a nearly ubiquitous signaling molecule important for numerous signaling pathways in human skin. We studied a novel class of mammalian adenylyl cyclase, the soluble adenylyl cyclase (sAC). We examined sAC localization in normal human skin and found it to be present in keratinocytes, melanocytes, mononuclear cells, eccrine ducts, and nerves. In normal skin, sAC keratinocyte staining was evenly distributed throughout the cell. However, in certain hyperproliferative disorders of the skin, including psoriasis, verruca vulgaris, and SCCIS on sun-damaged skin, sAC keratinocyte staining was predominantly nuclear. In contrast, in other hyperproliferative disorders, such as basal cell carcinoma, sAC staining was similar to normal human skin. Using a model of epithelial differentiation, we established that sAC migrates into the nucleus when differentiated cells are induced to reenter the cell cycle. Previous work had determined that nuclear sAC activates the cAMP-response-element-binding (CREB) transcription factor, and we found that in psoriasis lesions, nuclear sAC occurs concomitantly with activation of CREB. Hence, sAC may play a role in the pathogenesis of certain hyperproliferative skin disorders via modulation of gene expression.
Department of Dermatology, NYPH-Weill Cornell Medical Center, New York, New York, USA. jhzippin@nyp.org
Jonathan H
JH
Zippin
Paul A
PA
Chadwick
Lonny R
LR
Levin
Jochen
J
Buck
Cynthia M
CM
Magro
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004285:Dogs; D004817:Epidermis / Q000473:pathology / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology*; D007642:Keratosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000166:cytology; D021962:Membrane Microdomains / Q000378:metabolism; D008976:Molluscum Contagiosum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D012871:Skin Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012995:Solubility; D014158:Transcription, Genetic / Q000502:physiology; D014466:Ultraviolet Rays / Q000009:adverse effects
D000242:Cyclic AMP; D000262:Adenylyl Cyclases