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

Abstract

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.

Homozygosity mapping with SNP arrays identifiesTRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11)

“…The tissue expression pattern of TRIM32 has been reported (24)(25)(26) and is similar to the pattern of expression of other BBS genes. Expression of TRIM32 in the mammalian eye and hypothalamus has not been previously evaluated to our Shown are the cytogenetic location, the number of consecutive homozygous SNPs, and the physical interval size.…”

“…Independent of the data generated in this study, three separate lines of evidence suggest TRIM32 as the best BBS candidate gene in the 2.4-Mb interval. First, the expression pattern of TRIM32 is similar to the other known BBS genes (24)(25)(26). Second, there are three relevant knockout mouse models for genes within the linked interval: Pappa (31), Astn1 (paralogue of Astn2) (32), and Tlr4 (33).…”

E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis

“…13,14 TRIM32 overexpression was frequently observed in skin carcinoma, and head and neck squamous cell carcinoma, thereby suggesting a potential role of TRIM32 in tumorigenesis. 15,16 TRIM32 was reported to possess E3 Ub ligase activity, attributable to its RING finger. TRIM32 ubiquitinates dysbindin that may contribute to TRIM32's role in skeletal muscle and neuronal cell differentiation.…”

Regulation of the Drosophila lin‐41 homologue dappled by let‐7 reveals conservation of a regulatory mechanism within the LIN‐41 subclade

“…They have been shown to participate in numerous distinct processes, including roles in development, both normal and tumorous, asymmetric cell divisions and viral response (Arama et al, 2000;Horn et al, 2004;Bello et al, 2006;Betschinger et al, 2006;Lee et al, 2006;Sakuma et al, 2007) and see Table 2 in Meroni and Diez-Roux (2005), to name but a few. This protein superfamily is characterized by the presence of multiple protein-protein interaction domains, from which it has derived its name, that is, RING, B-box, and coiled-coil domains (Fig.…”