Pax-5 Protein Expression Is Regulated by Transcriptional 3′UTR Editing

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 & PRIME;end of the Pax-5 transcript is submitted to alternative polyadenylation (APA) and alternative splicing events. Using rapid amplification of cDNA ends (3 & PRIME;RACE) from polysomal fractions, we found that Pax-5 3 & PRIME; untranslated region (UTR) shortening correlates with increased ribosomal occupancy for translation. These observations were also validated using reporter gene assays with truncated 3 & PRIME;UTR regions cloned downstream of a luciferase gene. We also showed that Pax-5 3 & PRIME;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 & PRIME;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.

Automated summary

The expression of Pax-5 gene is associated with cancer lesions, including genetic mutations and post-transcriptional regulation alterations. This study reveals that Pax-5 transcript editing contributes to its aberrant expression and is linked to regulatory elements like miRNAs. Moreover, shorter Pax-5 3' untranslated region is related to advanced staging of hematopoietic cancers.