This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Harms, K. L.
Right arrow Articles by Chen, X.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Harms, K. L.
Right arrow Articles by Chen, X.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2005, p. 2014-2030, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.2014-2030.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The C Terminus of p53 Family Proteins Is a Cell Fate Determinant

Kelly Lynn Harms and Xinbin Chen*

Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama

Received 4 October 2004/ Accepted 29 November 2004

The p53 tumor suppressor is the most commonly mutated gene in human cancers. The ability of p53 to induce cell cycle arrest, apoptosis, DNA repair, and other p53-dependent activities is well known; however, the mechanism by which p53 induces a specific activity over another is unclear. Here, we showed that stringent regulation of and by p53 family isoforms facilitates differential target gene expression and thus determines cell fate. Through the use of engineered deletion mutants, we found that activation domain 2 is required for induction of the proapoptotic target gene insulin-like growth factor binding protein 3 (IGFBP3) by p53 and that the basic domain inhibits induction of this gene by p53. Thus, for the first time we provide evidence that the basic domain of p53 is inhibitory in vivo as has been determined in vitro. We also showed that the in vivo inhibitory activity of the basic domain depends upon activation domain 1, such that combined deletion of activation domain 1 and the basic domain was required to alleviate the inhibition by the basic domain. Importantly, deletion of the inhibitory functional domains, namely N-terminal activation domain 1 and the C-terminal basic domain, is paralleled in nature. We found that the IGFBP3 promoter was activated by p53({Delta}N{Delta}BD), which mimics a naturally occurring N- and C-terminally truncated human p53 isoform, and by p53AS, a C-terminally truncated murine p53 isoform generated through alternative splicing, but not by full-length human or murine p53. In addition, we found that the C termini of p63 and p73 inhibit the induction of IGFBP3, such that C-terminally truncated p63 and p73 isoforms induce the expression of IGFBP3, whereas full-length ones cannot. We also demonstrated that IGFBP3 is an important effector of the apoptosis induced by N- and C-terminally truncated p53, such that knockdown of IGFBP3 by using an IGFBP3 neutralizing antibody or IGFBP3 small interfering RNA partially rescues the cell death induced by N- and C-terminally truncated p53. In addition, we identified that histone deacetylase activity, not p53 DNA binding ability, governs the regulation of IGFBP3 by full-length p53 family proteins, as inhibition of histone deacetylases restores the induction of IGFBP3 by exogenous full-length p53, p63, and p73 proteins. Furthermore, we found that activation of p53 or inhibition of histone deacetylases alone was not sufficient to induce IGFBP3; however, combined treatment endowed endogenous p53 with this activity. To better understand the significance of this regulation, we performed a microarray study and identified several target genes differentially regulated by full-length p53 and p53 lacking the N-terminal activation domain 1 and the C-terminal basic domain. Taken together, our data suggest a novel mechanism by which p53 family proteins differentially regulate gene expression and provide an insight for designing a combined therapy for cancer treatment.

* Corresponding author. Mailing address: University of Alabama-Birmingham, Department of Cell Biology, MCLM 660, 1918 University Blvd., Birmingham, AL 35294. Phone: (205) 975-1798. Fax: (205) 934-0950. E-mail: xchen{at}uab.edu.

Molecular and Cellular Biology, March 2005, p. 2014-2030, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.2014-2030.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zhang, Y., Qian, Y., Lu, W., Chen, X. (2009). The G Protein-Coupled Receptor 87 Is Necessary for p53-Dependent Cell Survival in Response to Genotoxic Stress. Cancer Res. 69: 6049-6056 [Abstract] [Full Text]  
  • Yamada, P. M., Lee, K.-W. (2009). Perspectives in mammalian IGFBP-3 biology: local vs. systemic action. Am. J. Physiol. Cell Physiol. 296: C954-C976 [Abstract] [Full Text]  
  • Zhang, Y., Shu, L., Chen, X. (2008). Syntaxin 6, a Regulator of the Protein Trafficking Machinery and a Target of the p53 Family, Is Required for Cell Adhesion and Survival. J. Biol. Chem. 283: 30689-30698 [Abstract] [Full Text]  
  • Qian, Y., Chen, X. (2008). ID1, Inhibitor of Differentiation/DNA Binding, Is an Effector of the p53-dependent DNA Damage Response Pathway. J. Biol. Chem. 283: 22410-22416 [Abstract] [Full Text]  
  • Malaguarnera, R., Vella, V., Pandini, G., Sanfilippo, M., Pezzino, V., Vigneri, R., Frasca, F. (2008). TAp73{alpha} Increases p53 Tumor Suppressor Activity in Thyroid Cancer Cells via the Inhibition of Mdm2-Mediated Degradation. Mol Cancer Res 6: 64-77 [Abstract] [Full Text]  
  • Xu, Y., Zhang, J., Chen, X. (2007). The Activity of p53 Is Differentially Regulated by Brm- and Brg1-containing SWI/SNF Chromatin Remodeling Complexes. J. Biol. Chem. 282: 37429-37435 [Abstract] [Full Text]  
  • Yan, W., Chen, X. (2007). Targeted Repression of Bone Morphogenetic Protein 7, a Novel Target of the p53 Family, Triggers Proliferative Defect in p53-Deficient Breast Cancer Cells. Cancer Res. 67: 9117-9124 [Abstract] [Full Text]  
  • Lee, J., Basak, J. M., Demehri, S., Kopan, R. (2007). Bi-compartmental communication contributes to the opposite proliferative behavior of Notch1-deficient hair follicle and epidermal keratinocytes. Development 134: 2795-2806 [Abstract] [Full Text]  
  • Zhang, J., Chen, X. (2007). {Delta}Np73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA. Mol. Cell. Biol. 27: 3868-3880 [Abstract] [Full Text]  
  • Harms, K. L., Chen, X. (2007). Histone Deacetylase 2 Modulates p53 Transcriptional Activities through Regulation of p53-DNA Binding Activity. Cancer Res. 67: 3145-3152 [Abstract] [Full Text]  
  • Goldschneider, D., Horvilleur, E., Plassa, L.-F., Guillaud-Bataille, M., Million, K., Wittmer-Dupret, E., Danglot, G., The, H. d., Benard, J., May, E., Douc-Rasy, S. (2006). Expression of C-terminal deleted p53 isoforms in neuroblastoma. Nucleic Acids Res 34: 5603-5612 [Abstract] [Full Text]  
  • Shu, L., Yan, W., Chen, X. (2006). RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript. Genes Dev. 20: 2961-2972 [Abstract] [Full Text]  
  • Xu, Y., Chen, X. (2006). Glyoxalase II, a Detoxifying Enzyme of Glycolysis Byproduct Methylglyoxal and a Target of p63 and p73, Is a Pro-survival Factor of the p53 Family. J. Biol. Chem. 281: 26702-26713 [Abstract] [Full Text]  
  • Bhattacharyya, N., Pechhold, K., Shahjee, H., Zappala, G., Elbi, C., Raaka, B., Wiench, M., Hong, J., Rechler, M. M. (2006). Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus. J. Biol. Chem. 281: 24588-24601 [Abstract] [Full Text]  
  • Scoumanne, A., Chen, X. (2006). The Epithelial Cell Transforming Sequence 2, a Guanine Nucleotide Exchange Factor for Rho GTPases, Is Repressed by p53 via Protein Methyltransferases and Is Required for G1-S Transition.. Cancer Res. 66: 6271-6279 [Abstract] [Full Text]  
  • Yan, W., Chen, X. (2006). GPX2, a Direct Target of p63, Inhibits Oxidative Stress-induced Apoptosis in a p53-dependent Manner. J. Biol. Chem. 281: 7856-7862 [Abstract] [Full Text]  
  • Bourdon, J.-C., Fernandes, K., Murray-Zmijewski, F., Liu, G., Diot, A., Xirodimas, D. P., Saville, M. K., Lane, D. P. (2005). p53 isoforms can regulate p53 transcriptional activity. Genes Dev. 19: 2122-2137 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»