Loss of cell polarity is very common in invasive and metastatic tumours, but also in early stages of oncogenesis. In C. elegans the conserved Par genes control several proteins transducing polarity cues in the embryo. One of these transducers is the RNA‐binding protein ceMex‐3, an essential translational regulator involved in embryo development. Its human ortholog is Tino, firstly identified in our lab as a post‐transcriptional regulator, able to bind to the AU‐Rich Element (ARE) of bcl‐2 mRNA. The high conservation between ceMex‐3 and Tino suggests that also Tino could have an impact on mammalian embryogenesis, cell polarity and cancer. Par‐4 is a ceMex‐3 post‐translational regulator, its human ortholog LKB1 is responsible, if mutated, for the Peutz‐Jeghers cancer syndrome. Another liaison dangereuse co‐involves ceMex‐3 with gld‐1 gene, whose mammal ortholog is Quaking (Qki). Both ceMex‐3 and GLD‐1 co‐regulate common targets and if mutated induce onset of teratomas during gametogenesis.Here we show that QKI contributes to the negative regulation of Tino, confirming our hypothesis of evolutive conservation of Tino pathway. Furthermore, identification of Tino's target mRNAs and their consensus reveals that 50% of these mRNAs contains also Qki consensus, underlying the possibility that QKI and Tino co‐regulate common targets.Research supported by AIRC, MIUR and ECRF.
The Bcl-2 (B-cell lymphoma 2) antiapoptotic gene has been discovered in virtue of its over-expression occurring in B-cell leukemias/lymphomas carrying the 14;18 chromosomal translocation [t(14;18)], which places the Bcl-2 gene next to the immunoglobulin heavy chain (IgH) locus. In this condition, the transcription of the Bcl-2 moiety of the Bcl-2/IgH fusion gene is driven by the four enhancers located in 3' of the IgH moiety and is, therefore, excessive. This leads to overproduction of Bcl-2 protein, which confers a survival advantage that contributes to neoplastic transformation. Nevertheless, in most malignancies, comprising chronic lymphocytic leukemias, breast, prostate, colorectal and lung cancer, the over-expression of Bcl-2 does not imply chromosomal rearrangements, suggesting that alterations at post-transcriptional level could be involved. Collaborating with the group of Angelo Nicolin (University of Milan, Italy), we first disclosed the existence of a Bcl-2 post-transcriptional control based on interplay among an Adenine and uracil-Rich cis-acting Element (ARE) located in the 3'UTR of Bcl-2 mRNA and several trans-acting ARE-Binding Proteins (AUBPs). We also demonstrated its deregulation in human leukemias/lymphomas. In particular, we have identified some Bcl-2 AUBPs -such as AUF-1, TINO/hMex-3D, the Bcl-2 protein itself and ζ-Crystallin -and described their qualitative or quantitative alterations in cancer cells. Moreover, in the attempt to correct Bcl-2 deregulation in the human diseases characterized by defects or excesses of apoptosis, we have modulated exogenously Bcl-2 expression by means of different antisense strategies. In this research highlight, we briefly report our proceedings, in which a long non-coding Bcl-2/IgH antisense RNA (Bcl-2/IgH AS) we discovered in a serendipitous manner has played a key role.
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