Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes.
Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes.
复制标题
皮肤角质形成细胞中蛋白质异戊二烯基转移酶功能相关性的遗传学研究。
DOI：
10.1093/hmg/ddq036
复制
发表时间：
2010
影响因子：
3.5
通讯作者：
Young,StephenG
中科院分区：
文献类型：
--
作者：
Lee,Roger;Chang,SandyY;Trinh,Hung;Tu,Yiping;White,AndrewC;Davies,BrandonSJ;Bergo,MartinO;Fong,LorenG;Lowry,WilliamE;Young,StephenG
用法尼基或香叶基脂对蛋白质进行修饰，这一过程称为蛋白质预烯基化，促进了蛋白质与膜表面的相互作用。蛋白质预烯基化是由一对胞质酶，即蛋白质法呢基转移酶(FTase)和蛋白质香叶基香叶基转移酶I(GGTase-I)完成的。FTase和GGTase-I作为癌症和早衰症的治疗靶点已经引起了人们的兴趣，但关于这些酶对正常组织动态平衡的重要性的信息很少。一项研究实际上表明，FTase是完全可有可无的。为了探索蛋白质戊烯基转移酶对正常组织的重要性，我们使用Fntband Pggt1b(分别编码FTase和GGTase-I的β亚基)的条件性敲除等位基因和角蛋白14-Cre转基因来创建皮肤角质形成细胞中缺乏FTase或GGTase-I的小鼠。角质形成细胞特异性Fntb基因敲除小鼠是存活的，但出现了严重的脱发。虽然毛囊在发育过程中看起来正常，但出生后形态异常，超微结构和免疫组织化学研究显示许多凋亡细胞。Fntb基因缺陷小鼠的毛囊间表皮正常，但角质形成细胞在培养中不能增殖。不出所料，非法尼化的前层蛋白A和非法尼化的DNAJA1在Fntb缺陷的角质形成细胞中积累。角质形成细胞特异性的Pggt1基因敲除小鼠存活了发育，但出生后不久就死亡了。与缺失Fntb的角质形成细胞一样，Pggt1b缺失的角质形成细胞在培养中不能增殖。因此，FTase和GGTase-I都是维持皮肤角质形成细胞动态平衡所必需的。
The modification of proteins with farnesyl or geranylgeranyl lipids, a process called protein prenylation, facilitates interactions of proteins with membrane surfaces. Protein prenylation is carried out by a pair of cytosolic enzymes, protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type I (GGTase-I). FTase and GGTase-I have attracted interest as therapeutic targets for both cancer and progeria, but very little information exists on the importance of these enzymes for homeostasis of normal tissues. One study actually suggested that FTase is entirely dispensable. To explore the importance of the protein prenyltransferases for normal tissues, we used conditional knockout alleles forFntbandPggt1b(which encode the β-subunits of FTase and GGTase-I, respectively) and a keratin 14–Cre transgene to create mice lacking FTase or GGTase-I in skin keratinocytes. Keratinocyte-specificFntbknockout mice were viable but developed severe alopecia. Although hair follicles appeared normal during development, they were morphologically abnormal after birth, and ultrastructural and immunohistochemical studies revealed many apoptotic cells. The interfollicular epidermis ofFntb-deficient mice appeared normal; however, keratinocytes from these mice could not proliferate in culture. As expected, non-farnesylated prelamin A and non-farnesylated DNAJA1 accumulated inFntb-deficient keratinocytes. Keratinocyte-specificPggt1bknockout mice survived development but died shortly after birth. LikeFntb-deficient keratinocytes,Pggt1b-deficient keratinocytes did not proliferate in culture. Thus, both FTase and GGTase-I are required for the homeostasis of skin keratinocytes.