PHAPI/pp32 suppresses tumorigenesis by stimulating apoptosis.
PHAPI/pp32 is a tumor suppressor whose expression is altered in various human cancers. Although PHAPI possesses multiple biochemical activities, the molecular basis for its tumor-suppressive function has remained obscure. Recently we identified PHAPI as an apoptotic enhancer that stimulates apoptosome-mediated caspase activation. In this study, we defined the structural requirement for its activity to stimulate caspase activation using a series of truncation mutants of PHAPI. Further, utilizing these mutants, we provide evidence to support the model that the apoptotic activity of PHAPI is required for its tumor-suppressive capability. Consistently, pp32R1, a close homolog of PHAPI and yet an oncoprotein, is not able to stimulate caspase activation. A highly discrete region between these two proteins localizes to an essential caspase activation motif of PHAPI. Additionally, PHAPI is predominantly a nuclear protein, and it can translocate to the cytoplasm during apoptosis. Disruption of the nuclear localization signal of PHAPI caused a modest decrease of its tumor-suppressive function, indicating that nuclear localization of PHAPI contributes to, but is not essential for, tumor suppression.
Pan
Wei
W
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
da Graca
Li S
LS
Shao
Yufang
Y
Yin
Qian
Q
Wu
Hao
H
Jiang
Xuejun
X
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C087425:ANP32A protein, human; D051033:Apoptosis Inducing Factor; D047908:Intracellular Signaling Peptides and Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D020169:Caspases