title: Active Notch1 confers a transformed phenotype to primary human melanocytes.
abstract: The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (N(IC)) was exploited to determine if Notch activation is a "driving" event in melanocytic transformation or instead a "passenger" event associated with melanoma progression. N(IC)-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. N(IC)-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease.
authors: Wistar Institute, Philadelphia, PA 19104, USA.
authors: Chelsea C
authors: CC
authors: Pinnix
authors: John T
authors: JT
authors: Lee
authors: Zhao-Jun
authors: ZJ
authors: Liu
authors: Ronan
authors: R
authors: McDaid
authors: Klara
authors: K
authors: Balint
authors: Levi J
authors: LJ
authors: Beverly
authors: Patricia A
authors: PA
authors: Brafford
authors: Min
authors: M
authors: Xiao
authors: Benjamin
authors: B
authors: Himes
authors: Susan E
authors: SE
authors: Zabierowski
authors: Yumi
authors: Y
authors: Yashiro-Ohtani
authors: Katherine L
authors: KL
authors: Nathanson
authors: Ana
authors: A
authors: Bengston
authors: Pamela M
authors: PM
authors: Pollock
authors: Ashani T
authors: AT
authors: Weeraratna
authors: Brian J
authors: BJ
authors: Nickoloff
authors: Warren S
authors: WS
authors: Pear
authors: Anthony J
authors: AJ
authors: Capobianco
authors: Meenhard
authors: M
authors: Herlyn
mesh_terms: D051929:CD146 Antigen / Q000235:genetics / Q000502:physiology; D002455:Cell Division; D018450:Disease Progression; D052816:Foreskin / Q000166:cytology; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000473:pathology / Q000502:physiology*; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D010641:Phenotype; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D015854:Up-Regulation
chemical_list: D051929:CD146 Antigen; C497902:MCAM protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1