Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins.
Expression of the mammalian pyruvate kinase M (PKM) gene provides an important example of mutually exclusive splicing. We showed previously that the hnRNP proteins A1, A2 and PTB have a crucial role in this process. Here we provide evidence that concentration-dependent interactions involving a network of these proteins are sufficient to determine the outcome of PKM splicing. At high concentrations, such as those found in most cancer cells, hnRNPA1 binding to two sites in the upstream regulated exon (exon 9) orchestrates cooperative interactions leading to exon 9 exclusion. At lower concentrations, binding shifts to downstream intronic sites, such that exon 9 is included and exon 10 mainly excluded, with any mRNA including both exons degraded by nonsense-mediated decay. Together, our results provide a mechanism by which a few general factors control alternative splicing of a widely expressed transcript.
Department of Biological Sciences, Columbia University, New York, New York, USA.
Mo
M
Chen
Charles J
CJ
David
James L
JL
Manley
D017398:Alternative Splicing; D001483:Base Sequence; D001665:Binding Sites; D005091:Exons; D006367:HeLa Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism*; D006801:Humans; D007438:Introns; D009154:Mutation; D011770:Pyruvate Kinase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D034441:Heterogeneous-Nuclear Ribonucleoproteins; D011770:Pyruvate Kinase