RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties
RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties
复制标题
DOI：
10.1093/carcin/bgh003
复制
发表时间：
2004-02-01
期刊：
影响因子：
4.7
通讯作者：
Kulesz-Martin, M
中科院分区：
文献类型：
--
作者：
Horn, EJ;Albor, A;Kulesz-Martin, M
(Tri)在bar partite（m）下，在bar otif蛋白32，Trim 32，mRNA和蛋白表达在小鼠表皮癌发生模型的独立转化和致瘤性角质形成细胞中，在紫外线B（UVB）诱导的鳞状细胞癌（SCC）中，以及在类似于20 -25%的化学诱导的小鼠乳头状瘤和人头颈SCC中升高。这表明Trim 32表达升高经常发生在实验性表皮癌发生中，并且与人类癌症相关。转导的Trim 32在表皮体外转化测定中增加集落数，并且当皮肤移植到无胸腺nu/nu小鼠时在体内增加表皮增厚。这些作用与增殖无关，即使用12-O-十四烷酰佛波醇-13-乙酸酯治疗或肿瘤抑制因子p53的缺陷也不足以引起肿瘤发生。然而，转导的Trim 32抑制肿瘤坏死因子α（TNF α）对UVB诱导的体外角质形成细胞凋亡和暴露于UVB光的体内角质形成细胞移植物的凋亡反应的协同作用。与其RING结构域一致，Trim 32表现出E3-遍在蛋白连接酶的特征，包括本身被遍在蛋白质化并与遍在蛋白质化的蛋白质相互作用，并且在用TNFalpha/UVB处理培养的角质形成细胞后，这些特性增强。有趣的是，人类TRIM 32的错义点突变已经在肢带肌营养不良2 H型（一种常染色体隐性遗传疾病）中被报道。我们提出了一个模型，其中Trim 32作为E3-泛素连接酶的活性有利于通过阻断UVB诱导的TNF α凋亡信号而启动癌发生中的细胞存活。
(Tri) under bar partite (m) under bar otif 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 similar to20-25% 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.