LKB1 Catalytic Activity Contributes to Estrogen Receptor α Signaling
LKB1 Catalytic Activity Contributes to Estrogen Receptor α Signaling
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DOI：
10.1091/mbc.e08-11-1138
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发表时间：
2009-06-01
影响因子：
3.3
通讯作者：
Marignani, Paola A.
中科院分区：
文献类型：
--
作者：
Nath-Sain, Suchita;Marignani, Paola A.
肿瘤抑制因子丝氨酸-苏氨酸激酶LKB 1在Peutz-Jeghers综合征（PJS）和上皮癌（包括乳腺癌、卵巢癌、睾丸癌和前列腺癌等对肿瘤敏感的器官）中发生突变。乳腺癌患者的临床研究表明，LKB 1低表达与预后不良有关，而在PJS中，乳腺癌的风险与乳腺癌（BRCA）1/BRCA 2生殖系突变的风险相似。在这项研究中，我们研究了LKB 1在雌激素受体α（ER α）信号转导中的作用。我们首次证明LKB 1在细胞核中与ER α结合，在细胞核中它被募集到ER α响应基因的启动子。此外，与LKB 1催化缺陷突变体相比，LKB 1催化活性增强ER α反式激活。这一发现的意义在于，我们首次证明了LKB 1和ER α之间的一种新的功能联系。我们的发现将LKB 1置于ER α信号传导的共激活剂作用中，拓宽了这种肿瘤抑制激酶的科学范围，并为LKB 1作为开发乳腺癌新疗法的靶点奠定了基础。
The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome (PJS) and in epithelial cancers, including hormone-sensitive organs such as breast, ovaries, testes, and prostate. Clinical studies in breast cancer patients show low LKB1 expression is related to poor prognosis, whereas in PJS, the risk of breast cancer is similar to the risk from germline mutations in breast cancer (BRCA) 1/BRCA2. In this study, we investigate the role of LKB1 in estrogen receptor alpha (ER alpha) signaling. We demonstrate for the first time that LKB1 binds to ER alpha in the cell nucleus in which it is recruited to the promoter of ER alpha-responsive genes. Furthermore, LKB1 catalytic activity enhances ER alpha transactivation compared with LKB1 catalytically deficient mutants. The significance of our discovery is that we demonstrate for the first time a novel functional link between LKB1 and ER alpha. Our discovery places LKB1 in a coactivator role for ER alpha signaling, broadening the scientific scope of this tumor suppressor kinase and laying the groundwork for the use of LKB1 as a target for the development of new therapies against breast cancer.