Henrich Lorin M, Smith Jeffrey A, Kitt Danielle, Errington Timothy M, Nguyen Binh, Traish Abdulmaged M, Lannigan Deborah A
Department of Microbiology and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908, USA.
Mol Cell Biol. 2003 Sep;23(17):5979-88. doi: 10.1128/MCB.23.17.5979-5988.2003.
Estrogen receptor alpha (ER alpha) degradation is regulated by ubiquitination, but the signaling pathways that modulate ER alpha turnover are unknown. We found that extracellular signal-regulated kinase 7 (ERK7) preferentially enhances the destruction of ER alpha but not the related androgen receptor. Loss of ERK7 was correlated with breast cancer progression, and all ER alpha-positive breast tumors had decreased ERK7 expression compared to that found in normal breast tissue. In human breast cells, a dominant-negative ERK7 mutant decreased the rate of endogenous ER alpha degradation >4-fold in the presence of hormone and potentiated estrogen responsiveness. ERK7 targets the ER alpha ligand-binding domain for destruction by enhancing its ubiquitination. Thus, ERK7 is a novel regulator of estrogen responsiveness through its control of ER alpha turnover.
雌激素受体α（ERα）的降解受泛素化调节，但调节ERα周转的信号通路尚不清楚。我们发现细胞外信号调节激酶7（ERK7）优先增强ERα的降解，而不影响相关的雄激素受体。ERK7的缺失与乳腺癌进展相关，与正常乳腺组织相比，所有ERα阳性乳腺肿瘤中ERK7表达均降低。在人乳腺细胞中，显性负性ERK7突变体在有激素存在的情况下，使内源性ERα降解速率降低超过4倍，并增强了雌激素反应性。ERK7通过增强ERα的泛素化作用，靶向其配体结合域进行降解。因此，ERK7通过控制ERα周转，是雌激素反应性的新型调节因子。
