Abstract
The Trp53 tumor suppressor gene product (p53) functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates proapoptotic Bcl-2 proteins to permeabilize mitochondria and initiate apoptosis. Here, we demonstrate that a tripartite nexus between Bcl-xL, cytoplasmic p53, and PUMA coordinates these distinct p53 functions. After genotoxic stress, Bcl-xL sequestered cytoplasmic p53. Nuclear p53 caused expression of PUMA, which then displaced p53 from Bcl-xL, allowing p53 to induce mitochondrial permeabilization. Mutant Bcl-xL that bound p53, but not PUMA, rendered cells resistant to p53-induced apoptosis irrespective of PUMA expression. Thus, PUMA couples the nuclear and cytoplasmic proapoptotic functions of p53.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Apoptosis Regulatory Proteins
-
Apoptosis*
-
Cell Line, Tumor
-
Cell Nucleus / metabolism*
-
Cells, Cultured
-
Cytoplasm / metabolism*
-
DNA Damage
-
Gene Expression Regulation
-
Humans
-
Immunoprecipitation
-
Mice
-
Mice, Inbred C57BL
-
Mitochondria / metabolism
-
Models, Biological
-
Permeability
-
Protein Binding
-
Protein Structure, Tertiary
-
Proto-Oncogene Proteins / metabolism*
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
Recombinant Proteins / metabolism
-
Tumor Suppressor Protein p53 / metabolism*
-
Tumor Suppressor Proteins / chemistry
-
Tumor Suppressor Proteins / metabolism*
-
Ultraviolet Rays
-
bcl-2-Associated X Protein
-
bcl-X Protein
Substances
-
Apoptosis Regulatory Proteins
-
BBC3 protein, human
-
BCL2L1 protein, human
-
Bcl2l1 protein, mouse
-
PUMA protein, mouse
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-bcl-2
-
Recombinant Proteins
-
Tumor Suppressor Protein p53
-
Tumor Suppressor Proteins
-
bcl-2-Associated X Protein
-
bcl-X Protein