Janknecht Ralf
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Oncogene. 2003 Feb 6;22(5):746-55. doi: 10.1038/sj.onc.1206185.
The transcription factor ER81 has been shown to be involved in ontogenesis and breast tumor formation. ER81 is activated by many signals through phosphorylation directly mediated by mitogen-activated protein kinases (MAPKs), but also by an unknown protein kinase(s). Here, mitogen- and stress-activated protein kinase 1 (MSK1), which itself is directly activated by distinct classes of MAPKs, is identified to regulate ER81 function. MSK1 expression enhances ER81-dependent transcription upon stimulation of especially the p38-MAPK pathway. Two serine residues in ER81 are phosphorylated by MSK1, and mutating these serine residues to alanines dramatically diminishes the ability of MSK1 to stimulate ER81. However, mutation of the MSK1 phosphorylation sites in ER81 does not completely abrogate the ability of MSK1 to activate ER81 function, suggesting that MSK1 may also target cofactors of ER81. Consistently, MSK1 interacts with two homologous coactivators of ER81, CBP and p300, and stimulates the transactivation domains of CBP. Thus, MSK1 may regulate ER81-dependent transcription via direct phosphorylation of ER81 as well as via stimulation of CBP/p300, which might be important for ER81's normal function and during mammary tumor formation.
转录因子ER81已被证明参与个体发育和乳腺肿瘤形成。ER81可被多种信号激活，这些信号通过丝裂原活化蛋白激酶（MAPK）直接介导的磷酸化作用，也可被一种未知的蛋白激酶激活。在此，丝裂原和应激激活蛋白激酶1（MSK1）被确定可调节ER81的功能，MSK1自身可被不同类型的MAPK直接激活。特别是在p38-MAPK信号通路受到刺激时，MSK1的表达可增强ER81依赖的转录作用。ER81中的两个丝氨酸残基被MSK1磷酸化，将这些丝氨酸残基突变为丙氨酸可显著降低MSK1刺激ER81的能力。然而，ER81中MSK1磷酸化位点的突变并未完全消除MSK1激活ER81功能的能力，这表明MSK1可能还靶向ER81的辅因子。一致的是，MSK1与ER81的两个同源共激活因子CBP和p300相互作用，并刺激CBP的反式激活结构域。因此，MSK1可能通过对ER81的直接磷酸化以及对CBP/p300的刺激来调节ER81依赖的转录，这可能对ER81的正常功能以及乳腺肿瘤形成过程很重要。
