| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Molecular Biology, Pathobiology, and Genetics |
1 Abramson Family Cancer Research Institute, 2 Institute for Medicine and Engineering, 3 Cardiovascular Institute, and 4 Departments of Medicine, 5 Pathology and Laboratory Medicine, and 6 Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania
Requests for reprints: Michael S. Parmacek, Department of Medicine, University of Pennsylvania, 9123 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104. Phone: 215-662-3140; Fax: 215-349-8017; E-mail: michael.parmacek{at}uphs.upenn.edu.
Signaling through Notch receptors in the skin has been implicated in the differentiation, proliferation, and survival of keratinocytes, as well as in the pathogenesis of basal cell carcinoma (BCC). To determine the composite function of Notch receptor–mediated signaling in the skin and overcome potential redundancies between receptors, conditional transgenic mice were generated that express the pan-Notch inhibitor, dominant-negative Mastermind Like 1 (DNMAML1), to repress all canonical [CBF-1/Suppressor of hairless/LAG-1 (CSL)–dependent] Notch signaling exclusively in the epidermis. Here, we report that DNMAML1 mice display hyperplastic epidermis and spontaneously develop cutaneous squamous cell carcinoma (SCC) as well as dysplastic precursor lesions, actinic keratoses. Mice expressing epidermal DNMAML1 display enhanced accumulation of nuclear ß-catenin and cyclin D1 in suprabasilar keratinocytes and in lesional cells from SCCs, which was also observed in human cutaneous SCC. These results suggest a model wherein CSL-dependent Notch signaling confers protection against cutaneous SCC. The demonstration that inhibition of canonical Notch signaling in mice leads to spontaneous formation of SCC and recapitulates the disease in humans yields fundamental insights into the pathogenesis of SCC and provides a unique in vivo animal model to examine the pathobiology of cutaneous SCC and for evaluating novel therapies. (Cancer Res 2006; 66(15): 7438-44)
This article has been cited by other articles:
|
|
 |
|
  E. A. Klein and R. K. Assoian Transcriptional regulation of the cyclin D1 gene at a glance J. Cell Sci., December 1, 2008; 121(23): 3853 - 3857. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Zhang, Y. Yang, P. A. Zweidler-McKay, and D. P.M. Hughes Critical Role of Notch Signaling in Osteosarcoma Invasion and Metastasis Clin. Cancer Res., May 15, 2008; 14(10): 2962 - 2969. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Li, H. Wen, C. Brayton, P. Das, L. A. Smithson, A. Fauq, X. Fan, B. J. Crain, D. L. Price, T. E. Golde, et al. Epidermal Growth Factor Receptor and Notch Pathways Participate in the Tumor Suppressor Function of {gamma}-Secretase J. Biol. Chem., November 2, 2007; 282(44): 32264 - 32273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Proweller, A. C. Wright, D. Horng, L. Cheng, M. M. Lu, J. J. Lepore, W. S. Pear, and M. S. Parmacek Notch signaling in vascular smooth muscle cells is required to pattern the cerebral vasculature PNAS, October 9, 2007; 104(41): 16275 - 16280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Li, H. Wen, C. Brayton, F. M. Laird, G. Ma, S. Peng, L. Placanica, T. C. Wu, B. J. Crain, D. L. Price, et al. Moderate Reduction of {gamma}-Secretase Attenuates Amyloid Burden and Limits Mechanism-Based Liabilities J. Neurosci., October 3, 2007; 27(40): 10849 - 10859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Bolos, J. Grego-Bessa, and J. L. de la Pompa Notch Signaling in Development and Cancer Endocr. Rev., May 1, 2007; 28(3): 339 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Lefort, A. Mandinova, P. Ostano, V. Kolev, V. Calpini, I. Kolfschoten, V. Devgan, J. Lieb, W. Raffoul, D. Hohl, et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCK{alpha} kinases Genes & Dev., March 1, 2007; 21(5): 562 - 577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Blanpain, W. E. Lowry, H. A. Pasolli, and E. Fuchs Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes & Dev., November 1, 2006; 20(21): 3022 - 3035. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
