Functional analysis of the CYLD tumor suppressor

Summary

Principal Investigator: JULIDE CELEBI
Abstract: CYLD is a novel tumor suppressor gene that was discovered by positional cloning of the linkage interval for Familial Cylindromatosis(FC) on chromosome 16q12. FC is an autosomal dominantly inherited syndrome characterized by disfiguring skin appendage tumors, such as cylindromas, trichoepitheliomas and spiradenomas. Typically these tumors are located on the scalp and face,appear in childhood or early adulthood, and gradually increase in size and number throughout life. Moreover, malignant transformation of these tumors with locally invasive behavior as well as distant metastasis can occur. Germline mutations in CYLD have been demonstrated in families with FC, and loss of heterozygosity at the CYLD locus has been found in these neoplasms, suggesting that CYLD functions as a tumor suppressor. The protein product of CYLD is 956 amino acids and contains sequence motifs found in deubiquitinating enzymes and microtubule binding proteins. It is expressed in a variety of tissues, and of interest, its expression in the skin is observed in the epidermis as well as in the skin appendages. Mutations leading to gain of function of proto-oncogenes or loss of function of tumor suppressor genes result in tumor development. Tumor suppressor genes either inhibit proliferation, promote apoptosis, or enhance differentiation, and maintain genomic integrity via regulation of distinct cellular pathways, one of which is the NF-KB signaling pathway. Recent data suggests that CYLD has enzymatic activity to deubiquitinate target proteins. It has been shown to interact with several members of the NF-KB signaling pathway, such as TRAF-2, TRIP, and IKKy/NEMO, and negatively regulate NF-KB activation. However, the molecular and cellular mechanism(s) of CYLD tumor suppression is largely unknown. NF-KB signaling is essential for ectodermal organogenesis. NF-KB suppression results in severe defects in the development of epidermal appendages including hair follicles and sweat glands. In addition, abnormalities in NF-KB signaling play a role in epidermal neoplasia. However, the mechanisms of tumor development related to NF-KB signaling, and in particular the role of CYLD-dependent tumorigenesis, are not well understood. Our overall goal is to define the functions of CYLD in cutaneous tumorigenesis. We have identified a variety of mutations in the CYLD gene in patients with FC. However, the mutational data on CYLD is currently limited. In Aim 1, we will evaluate genotype and phenotype correlation in FC that will lead to a molecular-based understanding of the skin appendage tumors. As a crucial step in defining the mechanisms of CYLD-mediated tumor suppression, we will establish a mouse model for FC in Aim 2. And lastly, our Preliminary Studies demonstrate that CYLD is present in both the nucleus and the cytoplasm of HeLa cells at steady state and that leptomycin B treatment increases its nuclear localization. This observation suggests that CYLD constitutively shuttles between cytoplasmic and nuclear compartments in a CRMl-dependent manner. However, its role in the nucleus has not been defined. In Aim 3, we first plan to identify a functional nuclear export signal responsible for nucleo-cytoplasmic shuttling of CYLD and evaluate localization of CYLD during NF-KB activation. Second, to provide insights into its nuclear role, we will attempt to identify its interaction partners in the nucleus. We anticipate that significant insights into the pathway of CYLD regulated tumor suppression will arise in the course of these studies, thereby extending our understanding of tumorigenesis.
Funding Period: 2005-04-01 - 2010-01-31
more information: NIH RePORT

Top Publications

  1. ncbi B-RAF and melanocytic neoplasia
    Melissa Gill
    Department of Pathology, Columbia University, New York, New York 10032, USA
    J Am Acad Dermatol 53:108-14. 2005
  2. pmc Genetics of skin appendage neoplasms and related syndromes
    D A Lee
    Department of Dermatology, Columbia University Medical Center, New York, USA
    J Med Genet 42:811-9. 2005
  3. ncbi Are all melanomas the same? Spitzoid melanoma is a distinct subtype of melanoma
    David A Lee
    Department of Dermatology, Columbia University Medical Center, New York, NY 10032, USA
    Cancer 106:907-13. 2006
  4. ncbi CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes
    A L Young
    Department of Dermatology, Columbia University, New York, NY 10032, USA
    Clin Genet 70:246-9. 2006
  5. ncbi Influence of age on survival in childhood spitzoid melanomas
    Marlyanne Pol-Rodriquez
    Department of Dermatology, Columbia University Medical Center, New York, New York 10032, USA
    Cancer 109:1579-83. 2007
  6. ncbi CYLD mutations in familial skin appendage tumours
    S Saggar
    Department of Dermatology, Columbia University, New York, NY 10032, USA
    J Med Genet 45:298-302. 2008
  7. pmc Gab2-mediated signaling promotes melanoma metastasis
    Basil Horst
    Columbia University, Department of Pathology, New York, NY 10032, USA
    Am J Pathol 174:1524-33. 2009
  8. pmc GAB2 amplifications refine molecular classification of melanoma
    Karen A Chernoff
    Departments of Dermatology and Pathology and Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA
    Clin Cancer Res 15:4288-91. 2009

Detail Information

Publications8

  1. ncbi B-RAF and melanocytic neoplasia
    Melissa Gill
    Department of Pathology, Columbia University, New York, New York 10032, USA
    J Am Acad Dermatol 53:108-14. 2005
    ..High frequency of B-RAF gene mutations has recently been identified in benign melanocytic nevi and melanoma. This review focuses on clinical studies that evaluate the role of B-RAF in melanocytic neoplasia...
  2. pmc Genetics of skin appendage neoplasms and related syndromes
    D A Lee
    Department of Dermatology, Columbia University Medical Center, New York, USA
    J Med Genet 42:811-9. 2005
    ....
  3. ncbi Are all melanomas the same? Spitzoid melanoma is a distinct subtype of melanoma
    David A Lee
    Department of Dermatology, Columbia University Medical Center, New York, NY 10032, USA
    Cancer 106:907-13. 2006
    ..In this study, the authors evaluated the contribution of B-RAF and N-RAS mutations to the pathogenesis of Spitzoid melanomas...
  4. ncbi CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes
    A L Young
    Department of Dermatology, Columbia University, New York, NY 10032, USA
    Clin Genet 70:246-9. 2006
    ..Of interest, one of the affected individuals described in this report exhibits a severe phenotype illustrating the morbidity of the disorder...
  5. ncbi Influence of age on survival in childhood spitzoid melanomas
    Marlyanne Pol-Rodriquez
    Department of Dermatology, Columbia University Medical Center, New York, New York 10032, USA
    Cancer 109:1579-83. 2007
    ..Whereas a number of spitzoid melanomas with regional lymph node metastasis with no further progression have been reported, cases leading to widespread metastasis and fatal outcomes are also well documented...
  6. ncbi CYLD mutations in familial skin appendage tumours
    S Saggar
    Department of Dermatology, Columbia University, New York, NY 10032, USA
    J Med Genet 45:298-302. 2008
    ..Although described as distinct entities, recent studies suggest that they are within the spectrum of a single entity...
  7. pmc Gab2-mediated signaling promotes melanoma metastasis
    Basil Horst
    Columbia University, Department of Pathology, New York, NY 10032, USA
    Am J Pathol 174:1524-33. 2009
    ..Gab2 overexpression resulted in enhanced tumor growth and metastatic potential in vivo. These studies demonstrate a previously undefined role for Gab2 in melanoma tumor progression and metastasis...
  8. pmc GAB2 amplifications refine molecular classification of melanoma
    Karen A Chernoff
    Departments of Dermatology and Pathology and Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA
    Clin Cancer Res 15:4288-91. 2009
    ..We sought to determine the association of increased copy numbers of GAB2 among melanoma subtypes in the context of genetic alterations in BRAF, NRAS, and KIT...