Switched alternative splicing of oncogene CoAA during embryonal carcinoma stem cell differentiation.
MetadataShow full item record
AbstractAlternative splicing produces functionally distinct proteins participating in cellular processes including differentiation and development. CoAA is a coactivator that regulates transcription-coupled splicing and its own pre-mRNA transcript is alternatively spliced. We show here that the CoAA gene is embryonically expressed and alternatively spliced in multiple tissues to three splice variants, CoAA, CoAM and CoAR. During retinoic-acid-induced P19 stem cell differentiation, the expression of CoAA undergoes a rapid switch to its dominant negative splice variant CoAM in the cavity of the embryoid body. CoAM functionally inhibits CoAA, and their switched expression up-regulates differentiation marker Sox6. Using a CoAA minigene cassette, we find that the switched alternative splicing of CoAA and CoAM is regulated by the cis-regulating sequence upstream of the CoAA basal promoter. Consistent to this, we show that p54(nrb) and PSF induce CoAM splice variant through the cis-regulating sequence. We have previously shown that the CoAA gene is amplified in human cancers with a recurrent loss of this cis-regulating sequence. These results together suggest that the upstream regulatory sequence contributes to alternative splicing of the CoAA gene during stem cell differentiation, and its selective loss in human cancers potentially deregulates CoAA alternative splicing and alters stem cell differentiation.
CitationNucleic Acids Res. 2007 Mar 1; 35(6):1919-1932
- Functional pre- mRNA trans-splicing of coactivator CoAA and corepressor RBM4 during stem/progenitor cell differentiation.
- Authors: Brooks YS, Wang G, Yang Z, Smith KK, Bieberich E, Ko L
- Issue date: 2009 Jul 3
- Identification and characterization of RRM-containing coactivator activator (CoAA) as TRBP-interacting protein, and its splice variant as a coactivator modulator (CoAM).
- Authors: Iwasaki T, Chin WW, Ko L
- Issue date: 2001 Sep 7
- Gene amplification and associated loss of 5' regulatory sequences of CoAA in human cancers.
- Authors: Sui Y, Yang Z, Xiong S, Zhang L, Blanchard KL, Peiper SC, Dynan WS, Tuan D, Ko L
- Issue date: 2007 Feb 8
- Dual roles for coactivator activator and its counterbalancing isoform coactivator modulator in human kidney cell tumorigenesis.
- Authors: Kang YK, Schiff R, Ko L, Wang T, Tsai SY, Tsai MJ, O'Malley BW
- Issue date: 2008 Oct 1
- Sox6 overexpression causes cellular aggregation and the neuronal differentiation of P19 embryonic carcinoma cells in the absence of retinoic acid.
- Authors: Hamada-Kanazawa M, Ishikawa K, Nomoto K, Uozumi T, Kawai Y, Narahara M, Miyake M
- Issue date: 2004 Feb 27