title: TGFbeta activates mitogen- and stress-activated protein kinase-1 (MSK1) to attenuate cell death.
abstract: Transforming growth factor-β (TGFβ) binding to its receptor leads to intracellular phosphorylation of Smad2 and Smad3, which oligomerize with Smad4. These complexes accumulate in the nucleus and induce gene transcription. Here we describe mitogen- and stress-activated kinase 1 (MSK1) as an antagonist of TGFβ-induced cell death. Induction of MSK1 activity by TGFβ depends on Smad4 and p38 MAPK activation. Knockdown of GADD45, a Smad4-induced upstream regulator of p38 MAPK prevents TGFβ-induced p38 and MSK1 activity. MSK1 functionally regulates pro-apoptotic BH3-only BCL2 proteins, as MSK1 knockdown reduces Bad phosphorylation and enhances Noxa and Bim expression, leading to enhanced TGFβ-induced caspase-3 activity and cell death. This finding suggests that MSK1 represents a pro-survival pathway bifurcating downstream of p38 and antagonizes the established pro-apoptotic p38 MAPK function. Furthermore, EGF could reverse all the effects observed after MSK1 knockdown. Monitoring the status of MSK1 activity in cancer promises new therapeutic targets as inactivating both MSK1 and EGF signaling may (re)-sensitize cells to TGFβ-induced cell death.
authors.affiliation: Department of Molecular Cell Biology, and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands. lars.vdh@LICR.uu.se
authors.forename: Lars P
authors.initials: LP
authors.lastname: van der Heide
authors.forename: Maarten
authors.initials: M
authors.lastname: van Dinther
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D051025:bcl-Associated Death Protein; D048051:p38 Mitogen-Activated Protein Kinases; C494820:Bad protein, mouse; C000606776:Bcl2l11 protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C408009:Pmaip1 protein, mouse; C490810:Smad4 protein, mouse; C116919:mitogen and stress-activated protein kinase 1