The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes.
The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes.
复制标题
DOI：
10.1038/onc.2015.408
复制
发表时间：
2016-07-07
期刊：
影响因子：
8
通讯作者：
Palmero I
中科院分区：
文献类型：
--
作者：
Adrados I;Larrasa-Alonso J;Galarreta A;López-Antona I;Menéndez C;Abad M;Gil J;Moreno-Bueno G;Palmero I
细胞衰老是一种抗增殖反应，在肿瘤抑制和组织稳态中具有重要功能。在这里，我们表明，SIX1，同源框转录因子的SIX家族的成员，是一种新的抑制衰老。我们的数据表明，SIX1是特异性下调成纤维细胞后致癌压力和其他促衰老刺激，以及在衰老的皮肤癌前病变。人成纤维细胞中SIX1的沉默足以触发衰老，这是由p16INK4A介导的，并且缺乏典型的衰老相关分泌表型。有趣的是，SIX1相关衰老的特征还在于一组发育和分化相关基因的表达，这些基因与器官发生或人类肿瘤中的SIX1相关基因显著重叠，并在癌基因诱导的衰老中显示出一致的调节。从机制上讲，我们表明，衰老过程中SIX1的基因调控介导的，至少部分，通过与Polycomb抑制复合物的合作。总之，我们的研究结果确定了SIX1，一种在人类肿瘤中改变的关键发育调节因子，作为细胞衰老的关键阻遏物，提供了衰老，分化和肿瘤发生之间的新联系。
Cellular senescence is an antiproliferative response with essential functions in tumor suppression and tissue homeostasis. Here we show that SIX1, a member of the SIX family of homeobox transcriptional factors, is a novel repressor of senescence. Our data show that SIX1 is specifically downregulated in fibroblasts upon oncogenic stress and other pro-senescence stimuli, as well as in senescent skin premalignant lesions. Silencing of SIX1 in human fibroblasts suffices to trigger senescence, which is mediated by p16INK4A and lacks a canonical senescence-associated secretory phenotype. Interestingly, SIX1-associated senescence is further characterized by the expression of a set of development and differentiation-related genes that significantly overlap with genes associated to SIX1 in organogenesis or human tumors, and show coincident regulation in oncogene-induced senescence. Mechanistically, we show that gene regulation by SIX1 during senescence is mediated, at least in part, by cooperation with Polycomb repressive complexes. In summary, our results identify SIX1, a key development regulator altered in human tumors, as a critical repressor of cellular senescence, providing a novel connection between senescence, differentiation, and tumorigenesis.
登录
查看更多内容
影响因子：
3.7
作者：
Irelan, Jeffrey T.;del Arroyo, Ana Gutierrez;Chanda, Sumit K.
通讯作者：
Chanda, Sumit K.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
16
作者：
Chandra, Tamir;Kirschner, Kristina;Thuret, Jean-Yves;Pope, Benjamin D.;Ryba, Tyrone;Newman, Scott;Ahmed, Kashif;Samarajiwa, Shamith A.;Salama, Rafik;Carroll, Thomas;Stark, Rory;Janky, Rekin's;Narita, Masako;Xue, Lixiang;Chicas, Agustin;Nunez, Sabrina;Janknecht, Ralf;Hayashi-Takanaka, Yoko;Wilson, Michael D.;Marshall, Aileen;Odom, Duncan T.;Babu, M. Madan;Bazett-Jones, David P.;Tavare, Simon;Edwards, Paul A. W.;Lowe, Scott W.;Kimura, Hiroshi;Gilbert, David M.;Narita, Masashi
通讯作者：
Narita, Masashi
影响因子：
10.5
作者：
Barradas, Marta;Anderton, Emma;Gil, Jesus
通讯作者：
Gil, Jesus
影响因子：
7.8
作者：
Abad, Maria;Moreno, Alberto;Palmero, Ignacio
通讯作者：
Palmero, Ignacio