Journal Article

RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties

Elizabeth J. Horn, Amador Albor, Yuangang Liu, Sally El-Hizawi, Gretchen E. Vanderbeek, Melissa Babcock, G. Tim Bowden, Henry Hennings, Guillermina Lozano, Wendy C. Weinberg and Molly Kulesz-Martin

in Carcinogenesis

Volume 25, issue 2, pages 157-167
Published in print February 2004 | ISSN: 0143-3334
Published online February 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh003
RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties

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Tripartite motif protein 32, Trim32, mRNA and protein expression was elevated in independently transformed and tumorigenic keratinocytes of a mouse epidermal carcinogenesis model, in ultraviolet B (UVB)-induced squamous cell carcinomas (SCC), and in ∼20–25% of chemically induced mouse papillomas and human head and neck SCCs. This suggests that elevated Trim32 expression occurs frequently in experimental epidermal carcinogenesis and is relevant to human cancer. Transduced Trim32 increased colony number in an epidermal in vitro transformation assay and epidermal thickening in vivo when skin-grafted to athymic nu/nu mice. These effects were not associated with proliferation and were not sufficient for tumorigenesis, even with 12-O-tetradecanoylphorbol-13-acetate treatment or defects in the tumor suppressor p53. However, transduced Trim32 inhibited the synergistic effect of tumor necrosis factor α (TNFα) on UVB-induced apoptosis of keratinocytes in vitro and the apoptotic response of keratinocyte grafts exposed to UVB-light in vivo. Consistent with its RING domain, Trim32 exhibited characteristics of E3-ubiquitin ligases, including being ubiquitylated itself and interacting with ubiquitylated proteins, with increases in these properties following treatment of cultured keratinocytes with TNFα/UVB. Interestingly, missense point mutation of human TRIM32 has been reported in Limb-Girdle Muscular Dystrophy Type 2H, an autosomal recessive disease. We propose a model in which Trim32 activities as an E3-ubiquitin ligase favor initiated cell survival in carcinogenesis by blocking UVB-induced TNFα apoptotic signaling.

Keywords: EGF, epidermal growth factor; GFP, green fluorescent protein; GST, glutathione S-transferase; HCEM, high calcium Eagle's medium; HNSCC, head and neck SCC; LCEM, low calcium Eagle's medium; LGMD2H, Limb-Girdle Muscular Dystrophy type 2H; qPCR, quantitative real-time PCR; SBC, sunburn cell; SCC, squamous cell carcinoma; TPA, 12-O-tetradecanoylphorbol-13-acetate; TNFα, tumor necrosis factor alpha; Trim32, Tripartite motif protein 32; UVB, ultraviolet B

Journal Article.  8206 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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