CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals.
Recently a Drosophila p53 protein has been identified that mediates apoptosis via a novel pathway involving the activation of the Reaper gene and subsequent inhibition of the inhibitors of apoptosis (IAPs). The present study found that CIAP1, a major mammalian homolog of Drosophila IAPs, is irreversibly inhibited (cleaved) during p53-dependent apoptosis and this cleavage is mediated by a serine protease. Serine protease inhibitors that block CIAP1 cleavage inhibit p53-dependent apoptosis. Furthermore, activation of the p53 protein increases the transcription of the HTRA2 gene, which encodes a serine protease that interacts with CIAP1 and potentiates apoptosis. These results demonstrate that the mammalian p53 protein may activate apoptosis through a novel pathway functionally similar to that in Drosophila, which involves HTRA2 and subsequent inhibition of CIAP1 by cleavage.
Jin
Shengkan
S
Laboratory of Cancer Biology, Rockefeller University, New York, New York 10021, USA.
Kalkum
Markus
M
Overholtzer
Michael
M
Stoffel
Archontoula
A
Chait
Brian T
BT
Levine
Arnold J
AJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone; D004330:Drosophila; D029721:Drosophila Proteins / Q000502:physiology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D051379:Mice; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D012697:Serine Endopeptidases / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology; D013950:Thymus Gland; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C491641:ASF1A protein, human; C491640:ASF1B protein, human; C491639:Asf1b protein, mouse; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D013450:Sulfones; D016159:Tumor Suppressor Protein p53; C491642:asf1 protein, Drosophila; C086973:rpr protein, Drosophila; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D005047:Etoposide; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D020169:Caspases