Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 10 January 2003:
Vol. 299. no. 5604, pp. 223 - 226
DOI: 10.1126/science.1076807
Prev | Table of Contents | Next

Research Articles

Distinctive Roles of PHAP Proteins and Prothymosin-alpha in a Death Regulatory Pathway

Xuejun Jiang,12 Hyun-Eui Kim,12 Hongjun Shu,2 Yingming Zhao,2 Haichao Zhang,3 James Kofron,3 Jennifer Donnelly,3 Dave Burns,3 Shi-chung Ng,3 Saul Rosenberg,3 Xiaodong Wang12*

A small molecule, alpha -(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-alpha (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.

1 Howard Hughes Medical Institute,
2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3 Abbott Laboratories, D-460, AP10-LL, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
*   To whom correspondence should be addressed. E-mail: xwang{at}biochem.swmed.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Regenerative response in the pig liver remnant varies with the degree of resection and rise in portal pressure.
K. E. Mortensen, L. N. Conley, J. Hedegaard, T. Kalstad, P. Sorensen, C. Bendixen, and A. Revhaug (2008)
Am J Physiol Gastrointest Liver Physiol 294, G819-G830
   Abstract »    Full Text »    PDF »
Caspase-mediated cleavage of HuR in the cytoplasm contributes to pp32/PHAP-I regulation of apoptosis.
R. Mazroui, S. Di Marco, E. Clair, C. von Roretz, S. A. Tenenbaum, J. D. Keene, M. Saleh, and I.-E. Gallouzi (2008)
J. Cell Biol. 180, 113-127
   Abstract »    Full Text »    PDF »
Estrogen Suppresses Uterine Epithelial Apoptosis by Inducing Birc1 Expression.
Y. Yin, W.-W. Huang, C. Lin, H. Chen, A. MacKenzie, and L. Ma (2008)
Mol. Endocrinol. 22, 113-125
   Abstract »    Full Text »    PDF »
A Dimeric Smac/Diablo Peptide Directly Relieves Caspase-3 Inhibition by XIAP: DYNAMIC AND COOPERATIVE REGULATION OF XIAP BY SMAC/DIABLO.
Z. Gao, Y. Tian, J. Wang, Q. Yin, H. Wu, Y.-M. Li, and X. Jiang (2007)
J. Biol. Chem. 282, 30718-30727
   Abstract »    Full Text »    PDF »
XIAP Activity Dictates Apaf-1 Dependency for Caspase 9 Activation.
A. T. Ho, Q. H. Li, H. Okada, T. W. Mak, and E. Zacksenhaus (2007)
Mol. Cell. Biol. 27, 5673-5685
   Abstract »    Full Text »    PDF »
The crystal structure of the tumor suppressor protein pp32 (Anp32a): Structural insights into Anp32 family of proteins.
T. Huyton and C. Wolberger (2007)
Protein Sci. 16, 1308-1315
   Abstract »    Full Text »    PDF »
Identification of prothymosin-{alpha}1, the necrosis-apoptosis switch molecule in cortical neuronal cultures.
H. Ueda, R. Fujita, A. Yoshida, H. Matsunaga, and M. Ueda (2007)
J. Cell Biol. 176, 853-862
   Abstract »    Full Text »    PDF »
Diazonamide toxins reveal an unexpected function for ornithine {delta}-amino transferase in mitotic cell division.
G. Wang, L. Shang, A. W. G. Burgett, P. G. Harran, and X. Wang (2007)
PNAS 104, 2068-2073
   Abstract »    Full Text »    PDF »
Prothymosin {alpha} Interacts with Free Core Histones in the Nucleus of Dividing Cells.
G. Covelo, C. S. Sarandeses, C. Diaz-Jullien, and M. Freire (2006)
J. Biochem. 140, 627-637
   Abstract »    Full Text »    PDF »
Overexpression of the Oncoprotein Prothymosin {alpha} Triggers a p53 Response that Involves p53 Acetylation..
T. Kobayashi, T. Wang, M. Maezawa, M. Kobayashi, S. Ohnishi, K. Hatanaka, S. Hige, Y. Shimizu, M. Kato, M. Asaka, et al. (2006)
Cancer Res. 66, 3137-3144
   Abstract »    Full Text »    PDF »
Regulation of apoptosis by the p8/prothymosin {alpha} complex.
C. Malicet, V. Giroux, S. Vasseur, J. C. Dagorn, J. L. Neira, and J. L. Iovanna (2006)
PNAS 103, 2671-2676
   Abstract »    Full Text »    PDF »
Enhanced Sensitivity to Cytochrome c-Induced Apoptosis Mediated by PHAPI in Breast Cancer Cells.
Z. T. Schafer, A. B. Parrish, K. M. Wright, S. S. Margolis, J. R. Marks, M. Deshmukh, and S. Kornbluth (2006)
Cancer Res. 66, 2210-2218
   Abstract »    Full Text »    PDF »
Thanatos-Associated Protein 7 Associates with Template Activating Factor-I{beta} and Inhibits Histone Acetylation to Repress Transcription.
T. Macfarlan, J. B. Parker, K. Nagata, and D. Chakravarti (2006)
Mol. Endocrinol. 20, 335-347
   Abstract »    Full Text »    PDF »
Inaugural Article: Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1.
H.-E. Kim, F. Du, M. Fang, and X. Wang (2005)
PNAS 102, 17545-17550
   Abstract »    Full Text »    PDF »
New Approaches and Therapeutics Targeting Apoptosis in Disease.
U. Fischer and K. Schulze-Osthoff (2005)
Pharmacol. Rev. 57, 187-215
   Abstract »    Full Text »    PDF »
Transcriptional Profiling of Pig Embryogenesis by Using a 15-K Member Unigene Set Specific for Pig Reproductive Tissues and Embryos.
K.M. Whitworth, C. Agca, J.-G. Kim, R.V. Patel, G.K. Springer, N.J. Bivens, L.J. Forrester, N. Mathialagan, J.A. Green, and R.S. Prather (2005)
Biol Reprod 72, 1437-1451
   Abstract »    Full Text »    PDF »
Plasma membrane sequestration of apoptotic protease-activating factor-1 in human B-lymphoma cells: a novel mechanism of chemoresistance.
Y. Sun, S. Orrenius, S. Pervaiz, and B. Fadeel (2005)
Blood 105, 4070-4077
   Abstract »    Full Text »    PDF »
Phosphorylated Retinoblastoma Protein Complexes with pp32 and Inhibits pp32-mediated Apoptosis.
O. Adegbola and G. R. Pasternack (2005)
J. Biol. Chem. 280, 15497-15502
   Abstract »    Full Text »    PDF »
Nuclear Oncoprotein Prothymosin {alpha} Is a Partner of Keap1: Implications for Expression of Oxidative Stress-Protecting Genes.
R. N. Karapetian, A. G. Evstafieva, I. S. Abaeva, N. V. Chichkova, G. S. Filonov, Y. P. Rubtsov, E. A. Sukhacheva, S. V. Melnikov, U. Schneider, E. E. Wanker, et al. (2005)
Mol. Cell. Biol. 25, 1089-1099
   Abstract »    Full Text »    PDF »
Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors.
J. S. Ungerstedt, Y. Sowa, W.-S. Xu, Y. Shao, M. Dokmanovic, G. Perez, L. Ngo, A. Holmgren, X. Jiang, and P. A. Marks (2005)
PNAS 102, 673-678
   Abstract »    Full Text »    PDF »
Filtering of Ineffective siRNAs and Improved siRNA Design Tool.
S. M. Yiu, P. W. H. Wong, T.W. Lam, Y.C. Mui, H. F. Kung, M. Lin, and Y. T. Cheung (2005)
Bioinformatics 21, 144-151
   Abstract »    Full Text »    PDF »
Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis.
I. Zucchi, E. Mento, V. A. Kuznetsov, M. Scotti, V. Valsecchi, B. Simionati, E. Vicinanza, G. Valle, S. Pilotti, R. Reinbold, et al. (2004)
PNAS 101, 18147-18152
   Abstract »    Full Text »    PDF »
A Novel Estrogen Receptor {alpha}-Associated Protein Alters Receptor-Deoxyribonucleic Acid Interactions and Represses Receptor-Mediated Transcription.
M. A. Loven, R. E. Davis, C. D. Curtis, N. Muster, J. R. Yates, and A. M. Nardulli (2004)
Mol. Endocrinol. 18, 2649-2659
   Abstract »    Full Text »    PDF »
Protein Phosphatase 2A, a Negative Regulator of the ERK Signaling Pathway, Is Activated by Tyrosine Phosphorylation of Putative HLA Class II-associated Protein I (PHAPI)/pp32 in Response to the Antiproliferative Lectin, Jacalin.
L.-G. Yu, L. C. Packman, M. Weldon, J. Hamlett, and J. M. Rhodes (2004)
J. Biol. Chem. 279, 41377-41383
   Abstract »    Full Text »    PDF »
A Signaling Role of Histone-binding Proteins and INHAT Subunits pp32 and Set/TAF-I{beta} in Integrating Chromatin Hypoacetylation and Transcriptional Repression.
S. N. Kutney, R. Hong, T. Macfarlan, and D. Chakravarti (2004)
J. Biol. Chem. 279, 30850-30855
   Abstract »    Full Text »    PDF »
Pro-apoptotic Proteins Released from the Mitochondria Regulate the Protein Composition and Caspase-processing Activity of the Native Apaf-1/Caspase-9 Apoptosome Complex.
D. Twiddy, D. G. Brown, C. Adrain, R. Jukes, S. J. Martin, G. M. Cohen, M. MacFarlane, and K. Cain (2004)
J. Biol. Chem. 279, 19665-19682
   Abstract »    Full Text »    PDF »
Generation and Characterization of LANP/pp32 Null Mice.
P. Opal, J. J. Garcia, A. E. McCall, B. Xu, E. J. Weeber, J. D. Sweatt, H. T. Orr, and H. Y. Zoghbi (2004)
Mol. Cell. Biol. 24, 3140-3149
   Abstract »    Full Text »    PDF »
Role of caspases in male infertility.
T. M. Said, U. Paasch, H.-J. Glander, and A. Agarwal (2004)
Hum. Reprod. Update 10, 39-51
   Abstract »    Full Text »    PDF »
Mapmodulin/Leucine-rich Acidic Nuclear Protein Binds the Light Chain of Microtubule-associated Protein 1B and Modulates Neuritogenesis.
P. Opal, J. J. Garcia, F. Propst, A. Matilla, H. T. Orr, and H. Y. Zoghbi (2003)
J. Biol. Chem. 278, 34691-34699
   Abstract »    Full Text »    PDF »
Direct activation of the apoptosis machinery as a mechanism to target cancer cells.
J. T. Nguyen and J. A. Wells (2003)
PNAS 100, 7533-7538
   Abstract »    Full Text »    PDF »


ADVERTISEMENT
Click Me!

ADVERTISEMENT
Click Me!

To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)