女皇大学的研究人员们已揭示了与甲状腺癌相关细胞突变蛋白的作用。该发现为未来开发更加靶向的，甚至能治愈遗传性和非遗传性甲状腺癌的药物铺平了道路。     该论文的第一作者女皇大学病理学与分子医学系博士生Taranjit S. Gujral，描绘了突变的RET蛋白的3D模型，该蛋白参与调控癌性甲状腺肿块的发生。该模型使他能够推测和比该较蛋白的分子作用，并发现该蛋白比多发性内分泌腺瘤（MEN 2B） 2B综合征相关细胞中的正常蛋白活性高十倍，而此综合征为一种遗传性癌症综合征。      MEN 2B是一种显性遗传病--是该类综合征中最严重的一型--其特征为早发性甲状腺癌，目前采用手术联合其他治疗，包括放疗和化疗，但都不是非常敏感。此项研究提供了一个以该蛋白作用为特异靶点的有价值的工具，这可能有助于甲状腺癌治疗的发展。   原文出处： Thyroid Cancer Discovery Points to New Treatments, Prevention 11/15/06 -- The actions of a mutated protein in cells linked to thyroid cancer have been uncovered by researchers at Queen's University. The discovery paves the way for the future development of drugs to more effectively target, treat and possibly even prevent both inherited and non-inherited thyroid cancers. "We now know why this gene causes these tumours and can start looking at how best to target the mutant proteins so that the cells expressing them can be killed or stopped from growing," says Lois Mulligan, professor of pathology and molecular medicine with the Division of Cancer Biology and Genetics of the Queen's Cancer Research Institute. She is senior author of a study to be published November 15 in the journal Cancer Research. Taranjit S. Gujral, a Ph D student in Queen's Department of Pathology and Molecular Medicine and lead author on the paper, developed three-dimensional models of the mutated RET protein implicated in a condition causing cancerous thyroid tumours. The model allowed him to predict and compare the protein's molecular actions and to see that the protein was ten times more active than normal in cells associated with Multiple Endocrine Neoplasia 2B (MEN 2syndrome, an inherited cancer syndrome. Co-authors on the study include Vinay K. Singh and Zongchao Jia of Queen's Biochemistry Department. "It's like stepping on the gas in a car and getting way more gas than you bargained for," says Mulligan. "The mutation may cause some new actions but it chiefly does some actions more efficiently than normal." MEN 2B is a dominantly inherited condition - the most severe of its kind - and is characterized by the early onset of thyroid tumours, sometimes even affecting infants, and can also cause developmental abnormalities including elongated bones, gastric problems and bumpy lips. MEN 2B is currently treated with surgery, and other treatments, such as radiation and chemotherapy are not very effective. The study provides valuable tools for specific targeting of the actions of the protein that may aid in the development of anticancer therapies. The models created by Mr. Gujral, a Canadian Institutes of Health Research (CIHR) Trainee in Transdisciplinary Cancer Research and Protein Function Discovery, can be used further to help illuminate the actions of the protein with MEN 2B's other mutations. The research team credits the transdisciplinary approach and its benefits for providing fresh perspectives in generating the new understanding of RET's role in MEN 2B. Additional funding for the study came from the Canadian Cancer Society and the CIHR. Source: Queen's University, Kingston, Ontario http://www.bio.com/newsfeatures/newsfeatures_research.jhtml;jsessionid=YZUXJPJ1SVJPHR3FQLMSFEWHUWBNQIV0?cid=23700016 背景材料： 1、RET简介： ret 原癌基因首先是在其转化小鼠的NIH/ 3T3细胞中被发现的,它定位于10 号染色体10q11. 2 ,含21 个外显子,全长约60Kb ,编码一种跨膜的酪氨酸蛋白激酶受体,同其他酪氨酸蛋白激酶一样, ret蛋白也是由胞膜外配体结合区、跨膜区和胞内酪氨酸蛋白激酶功能区组成,其中胞膜外区分为半胱氨酸富集区和钙粘着蛋白样配基结合区两部分,与细胞间的信号转导有关,ret 蛋白的配体为胶质细胞衍生的神经营养因子(GDNF) 家族,包括GDNF、NINneuturin、ART artimin 和PSP persephin 四种,它们均通过糖基化的磷脂酰锚定蛋白与ret 蛋白结合,使ret蛋白的酪氨酸激酶功能区发生自动磷酸化并被激活,其下游信号可通过不同的途径来传导,包括磷脂酶C(PLC - γ) 、磷脂胱肌醇3 - 激酶(PI3 - k) 和Ras/有些分裂原激活蛋白激酶(MAP) 途径。从而调节细胞的正常生理功能,ret 原癌基因对神经内分泌系统、肾脏的发育,对调节神经嵴细胞的增殖、分化、迁移及肠神经系统的发育都起着重要的作用。 2、MEN2简介： MEN2 型(多发性内分泌腺瘤2 型) 是一种遗传性的内分泌肿瘤,根据受累的器官不同,可分为三种亚型:MEN2A(多发性内分泌腺瘤2A 型) 、MEN2B (多发性内分泌腺瘤2B 型) 、FMTC(家族性甲状腺髓样癌) ,它们共同的临床特征是甲状腺髓样癌。MEN2A型是最常见的形式,占MEN2 型的90 %以上,其中约有50 %的患者出现嗜铬细胞瘤,15%-30%的患者出现甲状旁腺增生,发病率约为1/ 25000。MEN2B 与MEN2A 一样,也是一种少见的遗传性肿瘤,它的特征除了甲状腺髓样癌和嗜铬细胞瘤外,还有典型的类马凡体综合征,唇舌的粘膜神经节瘤及肠梗阻,这种疾病的恶性程度更高并且预后不良。FMTC 仅仅以甲状腺髓样癌为特征,只有当家族中至少有4 个成员患有MTC 时,才被认为是FMTC。MEN2A 和FMTC 均与家族史有关,而50%MEN2B 与家族史无关。 3、与MEN 2B相关的的RET突变点： 在MEN 2B 中约有95 %的基因突变发生在16号外显子的918号密码子上,这种基因突变导致ATGC(蛋氨酸) 被Thr (苏氨酸) 所取代,在少数MEN 2B病例中为15号外显子的883号密码子发生突变,MEN2型中单个基因突变也可产生组织特异性的改变,其中634号密码子的基因突变与嗜铬细胞瘤的发生有关,而634号密码子中半胱氨酸被精氨酸取代的突变与甲状旁腺增生有关。 作者其他文献： Molecular Mechanisms of RET Receptor-Mediated Oncogenesis in Multiple Endocrine Neoplasia 2B. Cancer Res. 2006 Nov 15;66(22):10741-10749. Molecular Implications of RET Mutations for Pheochromocytoma Risk in Multiple Endocrine Neoplasia 2. Ann N Y Acad Sci. 2006 Aug;1073:234-40.   RET小知识：（pubmed gene） RET Official Symbol: RET and Name: ret proto-oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease) [Homo sapiens] Other Aliases: CDHF12, HSCR1, MEN2A, MEN2B, MTC1, PTC, RET-ELE1, RET51 Other Designations: RET transforming sequence; cadherin family member 12; fusion gene; hydroxyaryl-protein kinase; oncogene RET; proto-oncogene; receptor tyrosine kinase; ret proto-oncogene Chromosome: 10; Location: 10q11.2 MIM: 164761 GeneID: 5979   多发性内分泌腺瘤综合征 #162300 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB; MEN2B Alternative titles; symbols MEN IIB NEUROMATA, MUCOSAL, WITH ENDOCRINE TUMORS MUCOSAL NEUROMA SYNDROME MULTIPLE ENDOCRINE NEOPLASIA, TYPE III, FORMERLY; MEN3, FORMERLY WAGENMANN-FROBOESE SYNDROME GANGLIONEUROMATOSIS OF THE ALIMENTARY TRACT, INCLUDED Gene map locus 10q11.2 #171400 MULTIPLE ENDOCRINE NEOPLASIA, TYPE II; MEN2 Alternative titles; symbols MEN2A PHEOCHROMOCYTOMA AND AMYLOID-PRODUCING MEDULLARY THYROID CARCINOMA PTC SYNDROME SIPPLE SYNDROME THYROID CARCINOMA, FAMILIAL MEDULLARY, INCLUDED Gene map locus 10q11.2                                                                                                                      摘自《生物谷》