RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties.
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 approximately 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 alpha (TNFalpha) 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 TNFalpha/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 TNFalpha apoptotic signaling.
Department of Dermatology, Oregon Health and Science University, Portland, OR 97239, USA.
Elizabeth J
EJ
Horn
Amador
A
Albor
Yuangang
Y
Liu
Sally
S
El-Hizawi
Gretchen E
GE
Vanderbeek
Melissa
M
Babcock
G Tim
GT
Bowden
Henry
H
Hennings
Guillermina
G
Lozano
Wendy C
WC
Weinberg
Molly
M
Kulesz-Martin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016158:Genes, p53 / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D016038:Skin Transplantation; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014161:Transduction, Genetic; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014466:Ultraviolet Rays
D012333:RNA, Messenger; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C094027:TRIM32 protein, human; D044767:Ubiquitin-Protein Ligases; D013755:Tetradecanoylphorbol Acetate