BCR/ABL activates mdm2 mRNA translation via the La antigen

Abstract

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.

Translational research? Ribosome integrity and a new p53 tumor suppressor checkpoint

“…For example, the BCR/ABL oncoproteins activate MDM2 mRNA translation via the RNA binding protein La resulting in the downmodulation of p53. 8 Thus, cells are hardwired to respond to environmental stimuli by inducing the synthesis of protein translational machinery to coordinate cell growth (increase in cell size) with proliferation (increase in cell number). Uncoupling protein synthesis from cell growth and proliferation can result in tumorigenesis.…”

BCR/ABL, mRNA translation and apoptosis

“…72 Accordingly, Northern blot hybridization of polysome-and monosomeassociated RNA separated by linear sucrose gradient centrifugation revealed that mdm2 mRNA was predominantly in the polysome-associated fractions of BCR/ABL-expressing cells, whereas it was clearly shifted toward the monosome fractions after STI571 treatment. 72 Further analysis revealed that increased mdm2 mRNA translation in BCR/ABL cells was dependent on the integrity of a 27-base nucleotide sequence of mdm2 mRNA (located between the second uORF and 36 nucleotide upstream of the main AUG) which specifically interacts with the La antigen. 72 …”

“…For example, c/ebpb and p53 mRNAs, which reportedly undergo translational regulation [78][79][80][81][82] and are downregulated in BCR/ABL-transformed cells, 72,83 were less abundant (by oligonucleotidearray hybridization) in the polysome-associated mRNA fractions of untreated BCR/ABL-expressing cells, in which mdm2 mRNA levels were, instead, markedly increased. 72 Accordingly, Northern blot hybridization of polysome-and monosomeassociated RNA separated by linear sucrose gradient centrifugation revealed that mdm2 mRNA was predominantly in the polysome-associated fractions of BCR/ABL-expressing cells, whereas it was clearly shifted toward the monosome fractions after STI571 treatment. 72 Further analysis revealed that increased mdm2 mRNA translation in BCR/ABL cells was dependent on the integrity of a 27-base nucleotide sequence of mdm2 mRNA (located between the second uORF and 36 nucleotide upstream of the main AUG) which specifically interacts with the La antigen.…”

“…72 Further analysis revealed that increased mdm2 mRNA translation in BCR/ABL cells was dependent on the integrity of a 27-base nucleotide sequence of mdm2 mRNA (located between the second uORF and 36 nucleotide upstream of the main AUG) which specifically interacts with the La antigen. 72 …”

“…In BCR/ABL-expressing myeloid progenitor cell lines, high levels of BCR/ABL, as those observed in CML-BC, suppress differentiation, enhance survival and increase resistance to drug-induced apoptosis in part by enhancing the expression and activity of specific RNA binding proteins 72,[84][85][86][87] (Figure 2). Such an increase in the expression of these mRNA-binding proteins correlates with the levels of BCR/ABL and is sensitive to the treatment with imatinib mesylate.…”