Rangatia Janki, Vangala Rajani K, Singh Sheo M, Peer Zada Abdul A, Elsässer Annika, Kohlmann Alexander, Haferlach Torsten, Tenen Daniel G, Hiddemann Wolfgang, Behre Gerhard
Medicine III at University of Munich Hospital Grosshadern and GSF Research Center, Munich, Germany.
Oncogene. 2003 Jul 24;22(30):4760-4. doi: 10.1038/sj.onc.1206664.
Transcription factor C/EBPalpha induces normal myeloid differentiation, inactivation of C/EBPalpha leads to a differentiation block in acute myeloid leukemias (AML), and overexpression of C/EBPalpha results in AML growth arrest and differentiation. Recent reports suggest that C/EBPalpha is activated or inactivated via protein-protein interactions. We previously reported that C/EBPalpha needs to inactivate the proto-oncogene c-Jun via leucine zipper domain interaction in order to induce granulocytic differentiation. We, therefore, hypothesized that c-Jun expression might be elevated in AML and subsequently inactivate C/EBPalpha. In fact, compared to normal bone marrow mononuclear cells, c-Jun expression is increased in AML patient samples (Affymetrix expression microarray analysis, n=166). c-Jun binds to C/EBPalpha via the leucine zipper domains and prevents C/EBPalpha from DNA binding. Inactivation of C/EBPalpha by c-Jun is necessary for c-Jun to induce proliferation because c-Jun-induced proliferation can be prevented by ectopic overexpression of C/EBPalpha. The dominant-negative 30-kDa C/EBPalpha protein, found in AML, fails to downregulate c-Jun mRNA expression in AML patient samples. Thus, our data suggest a model for AML in which c-Jun promotes proliferation and prevents differentiation by inhibiting C/EBPalpha DNA binding via leucine zipper domain interaction. It might depend on the expression levels of C/EBPalpha and c-Jun, if inhibition of C/EBPalpha by c-Jun or if inhibition of c-Jun by C/EBPalpha is more predominant: proliferation versus differentiation; AML versus normal myeloid development.
转录因子C/EBPα可诱导正常髓系分化，C/EBPα失活会导致急性髓系白血病（AML）出现分化阻滞，而C/EBPα过表达则会导致AML生长停滞并分化。最近的报道表明，C/EBPα是通过蛋白质-蛋白质相互作用被激活或失活的。我们之前报道过，C/EBPα需要通过亮氨酸拉链结构域相互作用使原癌基因c-Jun失活，以诱导粒细胞分化。因此，我们推测c-Jun在AML中的表达可能会升高，进而使C/EBPα失活。事实上，与正常骨髓单个核细胞相比，AML患者样本中c-Jun的表达增加（Affymetrix表达微阵列分析，n = 166）。c-Jun通过亮氨酸拉链结构域与C/EBPα结合，阻止C/EBPα与DNA结合。c-Jun使C/EBPα失活对于c-Jun诱导增殖是必要 的，因为异位过表达C/EBPα可以阻止c-Jun诱导的增殖。在AML中发现的显性负性30 kDa C/EBPα蛋白，无法下调AML患者样本中c-Jun的mRNA表达。因此，我们的数据提示了一种AML模型，即c-Jun通过亮氨酸拉链结构域相互作用抑制C/EBPα与DNA结合，从而促进增殖并阻止分化。c-Jun对C/EBPα的抑制或C/EBPα对c-Jun的抑制何者占主导，可能取决于C/EBPα和c-Jun的表达水平：增殖与分化；AML与正常髓系发育。
