TY - JOUR
T1 - RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties
AU - Horn, Elizabeth J.
AU - Albor, Amador
AU - Liu, Yuangang
AU - El-Hizawi, Sally
AU - Vanderbeek, Gretchen E.
AU - Babcock, Melissa
AU - Bowden, G. Tim
AU - Hennings, Henry
AU - Lozano, Guillermo
AU - Weinberg, Wendy C.
AU - Kulesz-Martin, Molly
N1 - Funding Information:
We thank Dr James Cohen, Dr Peter Anderson, Dr Frank Warren and Dr Mark Wax, OHSU Otolaryngology—Head and Neck Surgery, for head and neck specimens. We are grateful to Dr Christopher Corless and Dr Clifton White for histopathological examination and helpful discussion, Barbara Lisafeld and Laura Lee for technical expertise, and Jodi Johnson for assistance with preparation of this manuscript. This study was supported by NIH CA31101, Oregon Health Sciences Foundation, OHSU Cancer Center grant CA69533, The Tartar Trust, Portland, OR, The Mark Diamond Research Foundation, Buffalo, NY and Roswell Park Cancer Institute center grant CA16056.
PY - 2004/2
Y1 - 2004/2
N2 - 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.
AB - 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.
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U2 - 10.1093/carcin/bgh003
DO - 10.1093/carcin/bgh003
M3 - Article
C2 - 14578165
AN - SCOPUS:10744221161
SN - 0143-3334
VL - 25
SP - 157
EP - 167
JO - Carcinogenesis
JF - Carcinogenesis
IS - 2
ER -