Tpl-2 induces apoptosis by promoting the assembly of protein complexes that contain caspase-9, the adapter protein Tvl-1, and procaspase-3.
The Tpl-2 proto-oncoprotein promotes cellular proliferation when overexpressed in a variety of tumor cell lines. Here, we present evidence that when overexpressed in immortalized non-transformed cells, Tpl-2 induces apoptosis by promoting the activation of caspase-3 via a caspase-9-dependent mechanism, and that apoptosis is enhanced when Tpl-2 is co-expressed with the newly identified ankyrin repeat protein Tvl-1. The activation of caspase-3 by caspase-9 is known to depend on the assembly of a multimolecular complex that includes Apaf-1 and caspase-9. Data presented here show that co-expression of Tpl-2 with Tvl-1 promotes the assembly of a complex that involves several proteins that bind Apaf-1 including Tvl-1, itself, Tpl-2 and phosphorylated procaspase-9. More important, procaspase-3, which under normal growth conditions is not associated with the complex, binds Tvl-1 conditionally in response to Tpl-2-generated apoptotic signals. The conditional association of procaspase-3 with Tvl-1 promotes the in vivo proteolytic maturation of procaspase-3 by caspase-9, a process casually linked to apoptosis.
Fox Chase Cancer Center, Philadelphia, Pensylvania, USA.
C
C
Patriotis
M G
MG
Russeva
J H
JH
Lin
S M
SM
Srinivasula
D Z
DZ
Markova
C
C
Tsatsanis
A
A
Makris
E S
ES
Alnemri
P N
PN
Tsichlis
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000502:physiology; D004792:Enzyme Precursors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors
C506592:APAF1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C506593:Apaf1 protein, mouse; C506594:Apaf1 protein, rat; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D011506:Proteins; D011518:Proto-Oncogene Proteins; C119810:Rfxank protein, mouse; D014157:Transcription Factors; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; C489843:Map3k8 protein, mouse; C080356:Map3k8 protein, rat; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases