Abstract
The Pax-5 gene encodes a transcription factor that is essential for B-cell commitment and maturation. However, Pax-5 deregulation is associated with various cancer lesions, notably hematopoietic cancers. Mechanistically, studies have characterized genetic alterations within the Pax-5 locus that result in either dominant oncogenic function or haploinsufficiency-inducing mutations leading to oncogenesis. Apart from these mutations, some examples of aberrant Pax-5 expression cannot be associated with genetic alterations. In the present study, we set out to elucidate potential alterations in post-transcriptional regulation of Pax-5 expression and establish that Pax-5 transcript editing represents an important means to aberrant expression. Upon the profiling of Pax-5 mRNA in leukemic cells, we found that the 3′end of the Pax-5 transcript is submitted to alternative polyadenylation (APA) and alternative splicing events. Using rapid amplification of cDNA ends (3′RACE) from polysomal fractions, we found that Pax-5 3′ untranslated region (UTR) shortening correlates with increased ribosomal occupancy for translation. These observations were also validated using reporter gene assays with truncated 3′UTR regions cloned downstream of a luciferase gene. We also showed that Pax-5 3′UTR editing has direct repercussions on regulatory elements such as miRNAs, which in turn impact Pax-5 protein expression. More importantly, we found that advanced staging of various hematopoietic cancer lesions relates to shorter Pax-5 3′UTRs. Altogether, our findings identify novel molecular mechanisms that account for aberrant expression and function of the Pax-5 oncogene in cancer cells. These findings also present new avenues for strategic intervention in Pax-5-mediated cancers.
Highlights
IntroductionResearch has enabled the elucidation of multiple regulatory pathways in aberrant gene expression leading to disease, presenting new therapeutic targets and strategies
Research has enabled the elucidation of multiple regulatory pathways in aberrant gene expression leading to disease, presenting new therapeutic targets and strategies.Adding complexity to these intricate networks are non-coding RNAs and the myriad of post-transcriptional modifications of mRNA targets
We demonstrate that the Pax-5 30 untranslated region (UTR) is significantly edited in cancer cells through the use of alternative polyadenylation (APA) or alternative splicing events, depending on the tissue type
Summary
Research has enabled the elucidation of multiple regulatory pathways in aberrant gene expression leading to disease, presenting new therapeutic targets and strategies. Adding complexity to these intricate networks are non-coding RNAs and the myriad of post-transcriptional modifications of mRNA targets. Reports show that aberrant alternative splicing is frequently associated with the development of cancer [4]. This is the case for the Pax-5 gene, which encodes a transcription factor essential for B-cell lineage commitment and maturation [5,6,7]. Given its pivotal regulatory function in B-cell development, Pax-5 is involved with the onset and progression of various hematological cancers and some carcinomas (reviewed in [8])
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
