Functions of TAp63 and p53 in restraining the development of metastatic cancer.
Functions of TAp63 and p53 in restraining the development of metastatic cancer.
复制标题
作者：
许多肿瘤含有p53肿瘤抑制基因突变，导致突变p53蛋白的表达。这种突变型p53蛋白在大多数情况下失去了野生型转录活性，并且还可以获得促进侵袭和转移的新功能。这些新功能的潜在机制之一涉及突变型p53干扰其他转录因子的能力，包括p53家族蛋白TAp 63。为了研究p53和TAp 63的同时耗竭是否可以重现突变型p53在体内表达的效果，我们使用了胰腺癌的小鼠模型，其中突变型p53的表达导致原发性肿瘤和转移灶的快速出现。如前所述，野生型（WT）p53的一个等位基因的丢失加速了肿瘤的发展。一个野生型p53等位基因突变为突变型p53并没有进一步加速肿瘤的发展，但促进了转移的形成。相比之下，TAp 63的缺失并没有显著加速肿瘤的发展或转移。然而，p53和TAp 63的同时耗尽导致快速肿瘤发展和转移潜力，尽管转移的发生率仍然低于突变型p53表达肿瘤中所见的发生率。来自这些小鼠的TAp 63/p53-null细胞在组织培养中也显示出增强的分散和侵入能力，如在突变型p53细胞中所观察到的。这些数据表明，在p53-null肿瘤中TAp 63的耗尽可以促进转移，并在一定程度上重演突变型p53表达的后果。
Many tumours harbour mutations in the p53 tumour-suppressor gene that result in the expression of a mutant p53 protein. This mutant p53 protein has, in most cases, lost wild-type transcriptional activity and can also acquire novel functions in promoting invasion and metastasis. One of the mechanisms underlying these novel functions involves the ability of the mutant p53 to interfere with other transcription factors, including the p53 family protein TAp63. To investigate whether simultaneous depletion of both p53 and TAp63 can recapitulate the effect of mutant p53 expression in vivo, we used a mouse model of pancreatic cancer in which the expression of mutant p53 resulted in the rapid appearance of primary tumours and metastases. As shown previously, loss of one allele of wild-type (WT) p53 accelerated tumour development. A change of one WT p53 allele into mutant p53 did not further accelerate tumour development, but did promote the formation of metastasis. By contrast, loss of TAp63 did not significantly accelerate tumour development or metastasis. However, simultaneous depletion of p53 and TAp63 led to both rapid tumour development and metastatic potential, although the incidence of metastases remained lower than that seen in mutant p53-expressing tumours. TAp63/p53-null cells derived from these mice also showed an enhanced ability to scatter and invade in tissue culture as was observed in mutant p53 cells. These data suggest that depletion of TAp63 in a p53-null tumour can promote metastasis and recapitulate—to some extent—the consequences of mutant p53 expression.
登录
查看更多内容
影响因子：
28.2
作者：
Collisson EA;Trejo CL;Silva JM;Gu S;Korkola JE;Heiser LM;Charles RP;Rabinovich BA;Hann B;Dankort D;Spellman PT;Phillips WA;Gray JW;McMahon M
通讯作者：
McMahon M
影响因子：
4.7
作者：
Edward, M;Gillan, C;Tammi, RH
通讯作者：
Tammi, RH
影响因子：
--
作者：
Bergholz, Johann;Xiao, Zhi-Xiong
通讯作者：
Xiao, Zhi-Xiong
影响因子：
14.9
作者：
Mangiulli M;Valletti A;Caratozzolo MF;Tullo A;Sbisà E;Pesole G;D'Erchia AM
通讯作者：
D'Erchia AM
影响因子：
21.3
作者：
Guo, Xuecui;Keyes, William M.;Papazoglu, Cristian;Zuber, Johannes;Li, Wangzhi;Lowe, Scott W.;Vogel, Hannes;Mills, Alea A.
通讯作者：
Mills, Alea A.