Trotta Rossana, Vignudelli Tatiana, Candini Olivia, Intine Robert V, Pecorari Luisa, Guerzoni Clara, Santilli Giorgia, Byrom Mike W, Goldoni Silvia, Ford Lance P, Caligiuri Michael A, Maraia Richard J, Perrotti Danilo, Calabretta Bruno
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA 19107, USA.
Cancer Cell. 2003 Feb;3(2):145-60. doi: 10.1016/s1535-6108(03)00020-5.
In a BCR/ABL-expressing myeloid precursor cell line, p53 levels were markedly downmodulated. Expression of MDM2, the negative regulator of p53, was upregulated in a tyrosine kinase-dependent manner in growth factor-independent BCR/ABL-expressing cells, and in accelerated phase and blast crisis CML samples. Increased MDM2 expression was associated with enhanced mdm2 mRNA translation, which required the interaction of the La antigen with mdm2 5' UTR. Expression of MDM2 correlated with that of La and was suppressed by La siRNAs and by a dominant negative La mutant, which also enhanced the susceptibility to drug-induced apoptosis of BCR/ABL-transformed cells. By contrast, La overexpression led to increased MDM2 levels and enhanced resistance to apoptosis. Thus, La-dependent activation of mdm2 translation might represent an important molecular mechanism involved in BCR/ABL leukemogenesis.
在一个表达BCR/ABL的髓系前体细胞系中，p53水平明显下调。p53的负调控因子MDM2的表达，在不依赖生长因子的表达BCR/ABL的细胞中，以及在加速期和急变期慢性粒细胞白血病（CML）样本中，以酪氨酸激酶依赖的方式上调。MDM2表达增加与mdm2 mRNA翻译增强相关，这需要La抗原与mdm2 5'非翻译区（UTR）相互作用。MDM2的表达与La的表达相关，并被La小干扰RNA（siRNAs）和显性负性La突变体抑制，这也增强了BCR/ABL转化细胞对药物诱导凋亡的敏感性。相比之下，La过表达导致MDM2水平升高并增强了对凋亡的抗性。因此，La依赖的mdm2翻译激活可能是参与BCR/ABL白血病发生的一个重要分子机制。
