Pax-5 Protein Expression Is Regulated by Transcriptional 3′UTR Editing
| Autor: | Annie-Pier Beauregard, Brandon Hannay, Ehsan Gharib, Nicolas Crapoulet, Nicholas Finn, Roxann Guerrette, Amélie Ouellet, Gilles A. Robichaud |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities animal structures QH301-705.5 Pax-5 B-cell Polyadenylation Article 03 medical and health sciences alternative splicing 0302 clinical medicine Cell Line Tumor Humans cancer RNA Messenger Biology (General) 3' Untranslated Regions Cells Cultured 030304 developmental biology Gene Editing 0303 health sciences B-Lymphocytes microRNA alternative polyadenylation PAX5 Transcription Factor General Medicine 3′UTR editing 3. Good health body regions 030220 oncology & carcinogenesis Polyribosomes Protein Biosynthesis embryonic structures sense organs |
| Zdroj: | Cells, Vol 11, Iss 76, p 76 (2022) Cells; Volume 11; Issue 1; Pages: 76 Cells |
| ISSN: | 2073-4409 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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