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Distinctive Roles of PHAP Proteins and Prothymosin-α in a Death Regulatory Pathway
Abstract
A small molecule, α-(trichloromethyl)-4-pyridineethanol (PETCM), was identified by high-throughput screening as an activator of caspase-3 in extracts of a panel of cancer cells. PETCM was used in combination with biochemical fractionation to identify a pathway that regulates mitochondria-initiated caspase activation. This pathway consists of tumor suppressor putative HLA-DR–associated proteins (PHAP) and oncoprotein prothymosin-α (ProT). PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. PETCM relieved ProT inhibition and allowed apoptosome formation at a physiological concentration of deoxyadenosine triphosphate. Elimination of ProT expression by RNA interference sensitized cells to ultraviolet irradiation–induced apoptosis and negated the requirement of PETCM for caspase activation. Thus, this chemical-biological combinatory approach has revealed the regulatory roles of oncoprotein ProT and tumor suppressor PHAP in apoptosis.
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Cited by
Mitochondria and cell death: outer membrane permeabilization and beyond
Tait, S. W. G., & Green, D. R. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2952 · Cited by 2,593
The apoptosome: Signalling platform of cell death
Riedl, S. J., & Salvesen, G. S. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2153 · Cited by 1,097
Mitochondrial Regulation of Cell Death
Tait, S. W. G., & Green, D. R. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008706 · Cited by 530
Ungerstedt, J. S., Sowa, Y., Xu, W.-S., Shao, Y., Dokmanovic, M., Perez, G., Ngo, L., Holmgren, A., Jiang, X., & Marks, P. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408732102 · Cited by 503
Self-citationThe Concise Guide to PHARMACOLOGY 2013/14: Enzymes
Alexander, S. P. H., Benson, H. E., Faccenda, E., Pawson, A. J., Sharman, J. L., Spedding, M., Peters, J. A., Harmar, A. J., & Collaborators, C. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12451 · Cited by 425
Metadata
- Authors
- Jiang, X., Kim, H.-E., Shu, H., Zhao, Y., Zhang, H., Kofron, J., Donnelly, J., Burns, D., Ng, S.-C., Rosenberg, S., & Wang, X.
- Venue
- Science
- Published
- 2003-01-10
- Volume
- 299
- Issue
- 5604
- Pages
- 223-226
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2096043228
- Cited by
- 378
- References
- 0
- FWCI
- 12.87
- Type
- journal article
- Language
- en
- Open access
- closed
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- Jiang, X., Kim, H.-E., Shu, H., Zhao, Y., Zhang, H., Kofron, J., Donnelly, J., Burns, D., Ng, S.-C., Rosenberg, S., & Wang, X. (2003). Distinctive Roles of PHAP Proteins and Prothymosin-α in a Death Regulatory Pathway. Science. https://doi.org/10.1126/science.1076807
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