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Activin receptor-like kinase-7 induces apoptosis through activation of MAPKs in a Smad3-dependent mechanism in hepatoma cells.

Authors
Kim, BC; van Gelder, H; Kim, TA; Lee, HJ; Baik, KG; Chun, HH; Lee, DA; Choi, KS; Kim, SJ
Citation
The Journal of biological chemistry, 279(27):28458-28465, 2004
Journal Title
The Journal of biological chemistry
ISSN
0021-92581083-351X
Abstract
Activin receptor-like kinase (ALK)7 is a type I serine/threonine kinase receptor of the transforming growth factor (TGF)-beta family of proteins that has similar properties to other type I receptors when activated. To see whether ALK7 can induce apoptosis as can some of the other ALK proteins, we infected the FaO rat hepatoma cell line with adenovirus expressing a constitutively active form of the ALK7. Cells infected with active ALK7 adenovirus showed an apoptotic-positive phenotype, as opposed to those that were infected with a control protein. DNA fragmentation assays and fluorescence-activated cell sorter analysis also indicated that ALK7 infection induced apoptosis in FaO cells. We also confirmed this finding in Hep3B human hepatoma cells by transiently transfecting the constitutively active form of ALK7, ALK7(T194D). Investigation into the downstream targets and mechanisms involved in ALK7-induced apoptosis revealed that the TGF-beta signaling intermediates, Smad2 and -3, were activated, as well as the MAPKs JNK and p38. In addition, caspase-3 and -9 were also activated, and cytochrome c release from the mitochondria was observed. Short interfering RNA-mediated inhibition of Smad3 markedly suppressed ALK7-induced caspase-3 activation. Treatment with protein synthesis inhibitors or the expression of the dominant-negative form of the stress-activated protein/extracellular signal-regulated kinase 1 abolished not only JNK activation but apoptosis as well. Taken together, these results suggest that ALK7 induces apoptosis through activation of the traditional TGF-beta pathway components, thus resulting in new gene transcription and JNK and p38 activation that initiates cross-talk with the cellular stress death pathway and ultimately leads to apoptosis.
MeSH terms
Activin Receptors, Type I/*metabolismAdenoviridae/genetics/metabolismAnimals*ApoptosisBlotting, WesternCarcinoma, Hepatocellular/metabolism/*pathologyCaspase 3Caspase 9Caspases/metabolismCell LineCell Line, TumorCell SeparationCell SurvivalCytochromes c/metabolismDNA FragmentationDNA-Binding Proteins/*metabolismDose-Response Relationship, DrugFlow CytometryGenes, DominantGenetic VectorsHumans*MAP Kinase Signaling SystemMitogen-Activated Protein Kinases/metabolismPlasmids/metabolismRNA, Small Interfering/metabolismRatsSmad2 ProteinSmad3 ProteinTrans-Activators/*metabolismTransfectionTransforming Growth Factor beta/metabolismTransforming Growth Factor beta1p38 Mitogen-Activated Protein Kinases
DOI
10.1074/jbc.M313277200
PMID
15107418
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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