This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Gerdes, M. J. Articles by Vinson, C. Search for Related Content PubMed PubMed Citation Articles by Gerdes, M. J. Articles by Vinson, C.

Activator Protein-1 Activity Regulates Epithelial Tumor Cell Identity

¹ Laboratory of Cellular Carcinogenesis and Tumor Promotion and ² Laboratory of Metabolism, National Cancer Institute, Center for Cancer Research, Bethesda, Maryland

Requests for reprints: Stuart H. Yuspa, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Center for Cancer Research, Bldg. 37 Rm. 4068A, Bethesda, MD 20892. Phone: 301-496-2162; Fax: 301-496-8709; E-mail: yuspas{at}mail.nih.gov or Charles Vinson, Laboratory of Metabolism, National Cancer Institute, Center for Cancer Research, Bldg. 37, Rm 3128, Bethesda, MD 20892. Phone: 301-496-8753, Fax: 301-496-8419; E-mail: Vinsonc{at}mail.nih.gov.

To examine the consequences of inhibiting activator protein-1 (AP-1) transcription factors in skin, transgenic mice were generated, which use the tetracycline system to conditionally express A-FOS, a dominant negative that inhibits AP-1 DNA binding. Older mice develop mild alopecia and hyperplasia of sebaceous glands, particularly around the eyes. When A-FOS was expressed during chemical-induced skin carcinogenesis, mice do not develop characteristic benign and malignant squamous lesions but instead develop benign sebaceous adenomas containing a signature mutation in the H-ras proto-oncogene. Inhibiting AP-1 activity after tumor formation caused squamous tumors to transdifferentiate into sebaceous tumors. Furthermore, reactivating AP-1 in sebaceous tumors results in a reciprocal transdifferentiation into squamous tumors. In both cases of transdifferentiation, individual cells express molecular markers for both cell types, indicating individual tumor cells have the capacity to express multiple lineages. Molecular characterization of cultured keratinocytes and tumor material indicates that AP-1 regulates the balance between the wnt/ß-catenin and hedgehog signaling pathways that determine squamous and sebaceous lineages, respectively. Chromatin immunoprecipitation analysis indicates that c-Jun binds several wnt promoters, which are misregulated by A-FOS expression, suggesting that members of the wnt pathway can be a primary targets of AP-1 transcriptional regulation. Thus, AP-1 activity regulates tumor cell lineage and is essential to maintain the squamous tumor cell identity. (Cancer Res 2006; 66(15): 7578-88)

This article has been cited by other articles:

				A. Saadeddin, R. Babaei-Jadidi, B. Spencer-Dene, and A. S. Nateri The Links between Transcription, {beta}-catenin/JNK Signaling, and Carcinogenesis Mol. Cancer Res., August 1, 2009; 7(8): 1189 - 1196. [Abstract] [Full Text] [PDF]

				J. Rozenberg, V. Rishi, A. Orosz, J. Moitra, A. Glick, and C. Vinson Inhibition of CREB Function in Mouse Epidermis Reduces Papilloma Formation Mol. Cancer Res., May 1, 2009; 7(5): 654 - 664. [Abstract] [Full Text] [PDF]

				M. Durchdewald, J. Guinea-Viniegra, D. Haag, A. Riehl, P. Lichter, M. Hahn, E. F. Wagner, P. Angel, and J. Hess Podoplanin Is a Novel Fos Target Gene in Skin Carcinogenesis Cancer Res., September 1, 2008; 68(17): 6877 - 6883. [Abstract] [Full Text] [PDF]

				K. S. Suh, M. Mutoh, T. Mutoh, L. Li, A. Ryscavage, J. M. Crutchley, R. A. Dumont, C. Cheng, and S. H. Yuspa CLIC4 mediates and is required for Ca2+-induced keratinocyte differentiation J. Cell Sci., August 1, 2007; 120(15): 2631 - 2640. [Abstract] [Full Text] [PDF]

				W. J. Oh, V. Rishi, A. Orosz, M. J. Gerdes, and C. Vinson Inhibition of CCAAT/Enhancer Binding Protein Family DNA Binding in Mouse Epidermis Prevents and Regresses Papillomas Cancer Res., February 15, 2007; 67(4): 1867 - 1876. [Abstract] [Full Text] [PDF]