p38-dependent phosphorylation of the mRNA decay-promoting factor KSRP controls the stability of select myogenic transcripts.
Transcriptional and posttranscriptional processes regulate expression of genetic networks in response to environmental cues. The extracellular signal-activated p38 MAP kinase (p38) pathway plays a fundamental role in conversion of myoblasts to differentiated myocytes. p38 phosphorylates specific transcription factors and chromatin-associated proteins promoting assembly of the myogenic transcriptome. Here, we demonstrate that p38 alpha and beta isoforms also control muscle-gene expression posttranscriptionally, by stabilizing critical myogenic transcripts. KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery. Overexpression of KSRP selectively impairs induction of ARE-containing early myogenic transcripts, without affecting p38-mediated transcriptional responses. Our results uncover an unanticipated role for KSRP in establishing a biochemical link between differentiation-activated p38 signaling and turnover of myogenic mRNAs.
Briata
Paola
P
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Forcales
Sonia Vanina
SV
Ponassi
Marco
M
Corte
Giorgio
G
Chen
Ching-Yi
CY
Karin
Michael
M
Puri
Pier Lorenzo
PL
Gherzi
Roberto
R
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000502:physiology*; D010766:Phosphorylation; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; C105789:KHSRP protein, human; C507913:Khsrp protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases