Format

Send to

Choose Destination
J Biol Chem. 2017 Aug 18;292(33):13745-13757. doi: 10.1074/jbc.M117.800318. Epub 2017 Jun 27.

Protein Sam68 regulates the alternative splicing of survivin DEx3.

Author information

1
From the Laboratories of Functional Genomics and.
2
Epigenetics, National Institute of Genomic Medicine (INMEGEN), 14610 Mexico City, Mexico.
3
From the Laboratories of Functional Genomics and gceballos@inmegen.gob.mx.
4
From the Laboratories of Functional Genomics and jmelendez@inmegen.gob.mx.

Abstract

Messenger RNA alternative splicing (AS) regulates the expression of a variety of genes involved in both physiological and pathological processes. AS of the anti-apoptotic and proliferation-associated survivin (BIRC5) gene generates six isoforms, which regulate key aspects of cancer initiation and progression. One of the isoforms is survivin DEx3, in which the exclusion of exon 3 generates a unique carboxyl terminus with specific anti-apoptotic functions. This isoform is highly expressed in advanced stages of breast and cervical tumors. Therefore, understanding the mechanisms that regulate survivin DEx3 mRNA AS is clearly important. To this end, we designed a minigene (M), and in combination with a series of deletions and site-directed mutations, we determined that the first 22 bp of exon 3 contain cis-acting elements that enhance the exclusion of exon 3 to generate the survivin DEx3 mRNA isoform. Furthermore, using pulldown assays, we discovered that Sam68 is a possible trans-acting factor that binds to this region and regulates exon 3 splicing. This result was corroborated using a cell line in which the Sam68 binding site in the survivin gene was mutated with the CRISPR/Cas system. This work provides the first clues regarding the regulation of survivin DEx3 mRNA splicing.

KEYWORDS:

KHDRBS1; Sam68; alternative splicing; cancer; cancer biology; gene regulation; survivin; survivin DEx3

PMID:
28655776
PMCID:
PMC5566528
DOI:
10.1074/jbc.M117.800318
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center