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 Hall, C.
Right arrow Articles by Adams, P. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hall, C.
Right arrow Articles by Adams, P. D.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2001, p. 1854-1865, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1854-1865.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

HIRA, the Human Homologue of Yeast Hir1p and Hir2p, Is a Novel Cyclin-cdk2 Substrate Whose Expression Blocks S-Phase Progression

Caitlin Hall,1 David M. Nelson,1 Xiaofen Ye,1 Kayla Baker,2 James A. DeCaprio,2 Steven Seeholzer,1 Marc Lipinski,3 and Peter D. Adams1,*

Fox Chase Cancer Center, Philadelphia, Pennsylvania 191111; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 021152; and Institut Gustave Roussy, Villejuif, France3

Received 20 July 2000/Returned for modification 11 September 2000/Accepted 7 December 2000

Substrates of cyclin-cdk2 kinases contain two distinct primary sequence motifs: a cyclin-binding RXL motif and one or more phosphoacceptor sites (consensus S/TPXK/R or S/TP). To identify novel cyclin-cdk2 substrates, we searched the database for proteins containing both of these motifs. One such protein is human HIRA, the homologue of two cell cycle-regulated repressors of histone gene expression in Saccharomyces cerevisiae, Hir1p and Hir2p. Here we demonstrate that human HIRA is an in vivo substrate of a cyclin-cdk2 kinase. First, HIRA bound to and was phosphorylated by cyclin A- and E-cdk2 in vitro in an RXL-dependent manner. Second, HIRA was phosphorylated in vivo on two consensus cyclin-cdk2 phosphoacceptor sites and at least one of these, threonine 555, was phosphorylated by cyclin A-cdk2 in vitro. Third, phosphorylation of HIRA in vivo was blocked by cyclin-cdk2 inhibitor p21cip1. Fourth, HIRA became phosphorylated on threonine 555 in S phase when cyclin-cdk2 kinases are active. Fifth, HIRA was localized preferentially to the nucleus, where active cyclin A- and E-cdk2 are located. Finally, ectopic expression of HIRA in cells caused arrest in S phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Phone: (215) 728-7108. Fax: (215) 728-3616. E-mail: pd_adams{at}fccc.edu.

Molecular and Cellular Biology, March 2001, p. 1854-1865, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1854-1865.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Meechan, D. W., Tucker, E. S., Maynard, T. M., LaMantia, A.-S. (2009). Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome. Proc. Natl. Acad. Sci. USA 106: 16434-16445 [Abstract] [Full Text]  
  • Deng, M., Li, F., Ballif, B. A., Li, S., Chen, X., Guo, L., Ye, X. (2009). Identification and Functional Analysis of a Novel Cyclin E/Cdk2 Substrate Ankrd17. J. Biol. Chem. 284: 7875-7888 [Abstract] [Full Text]  
  • Banumathy, G., Somaiah, N., Zhang, R., Tang, Y., Hoffmann, J., Andrake, M., Ceulemans, H., Schultz, D., Marmorstein, R., Adams, P. D. (2009). Human UBN1 Is an Ortholog of Yeast Hpc2p and Has an Essential Role in the HIRA/ASF1a Chromatin-Remodeling Pathway in Senescent Cells. Mol. Cell. Biol. 29: 758-770 [Abstract] [Full Text]  
  • Ambagala, A. P., Bosma, T., Ali, M. A., Poustovoitov, M., Chen, J. J., Gershon, M. D., Adams, P. D., Cohen, J. I. (2009). Varicella-Zoster Virus Immediate-Early 63 Protein Interacts with Human Antisilencing Function 1 Protein and Alters Its Ability To Bind Histones H3.1 and H3.3. J. Virol. 83: 200-209 [Abstract] [Full Text]  
  • DeRan, M., Pulvino, M., Greene, E., Su, C., Zhao, J. (2008). Transcriptional Activation of Histone Genes Requires NPAT-Dependent Recruitment of TRRAP-Tip60 Complex to Histone Promoters during the G1/S Phase Transition. Mol. Cell. Biol. 28: 435-447 [Abstract] [Full Text]  
  • White, A. E., Leslie, M. E., Calvi, B. R., Marzluff, W. F., Duronio, R. J. (2007). Developmental and Cell Cycle Regulation of the Drosophila Histone Locus Body. Mol. Biol. Cell 18: 2491-2502 [Abstract] [Full Text]  
  • Corsino, P., Davis, B., Law, M., Chytil, A., Forrester, E., Norgaard, P., Teoh, N., Law, B. (2007). Tumors Initiated by Constitutive Cdk2 Activation Exhibit Transforming Growth Factor {beta} Resistance and Acquire Paracrine Mitogenic Stimulation during Progression. Cancer Res. 67: 3135-3144 [Abstract] [Full Text]  
  • Ye, X., Zerlanko, B., Zhang, R., Somaiah, N., Lipinski, M., Salomoni, P., Adams, P. D. (2007). Definition of pRB- and p53-Dependent and -Independent Steps in HIRA/ASF1a-Mediated Formation of Senescence-Associated Heterochromatin Foci. Mol. Cell. Biol. 27: 2452-2465 [Abstract] [Full Text]  
  • Zhang, R., Chen, W., Adams, P. D. (2007). Molecular Dissection of Formation of Senescence-Associated Heterochromatin Foci. Mol. Cell. Biol. 27: 2343-2358 [Abstract] [Full Text]  
  • Zhang, R., Liu, S.-t., Chen, W., Bonner, M., Pehrson, J., Yen, T. J., Adams, P. D. (2007). HP1 Proteins Are Essential for a Dynamic Nuclear Response That Rescues the Function of Perturbed Heterochromatin in Primary Human Cells. Mol. Cell. Biol. 27: 949-962 [Abstract] [Full Text]  
  • Tsai, H.-K., Lu, H. H.-S., Li, W.-H. (2005). Statistical methods for identifying yeast cell cycle transcription factors. Proc. Natl. Acad. Sci. USA 102: 13532-13537 [Abstract] [Full Text]  
  • Ahmad, A., Kikuchi, H., Takami, Y., Nakayama, T. (2005). Different Roles of N-terminal and C-terminal Halves of HIRA in Transcription Regulation of Cell Cycle-related Genes That Contribute to Control of Vertebrate Cell Growth. J. Biol. Chem. 280: 32090-32100 [Abstract] [Full Text]  
  • Dash, B. C., El-Deiry, W. S. (2005). Phosphorylation of p21 in G2/M Promotes Cyclin B-Cdc2 Kinase Activity. Mol. Cell. Biol. 25: 3364-3387 [Abstract] [Full Text]  
  • Huang, Y., Chang, Y., Wang, X., Jiang, J., Frank, S. J. (2004). Growth Hormone Alters Epidermal Growth Factor Receptor Binding Affinity via Activation of Extracellular Signal-Regulated Kinases in 3T3-F442A Cells. Endocrinology 145: 3297-3306 [Abstract] [Full Text]  
  • Blackwell, C., Martin, K. A., Greenall, A., Pidoux, A., Allshire, R. C., Whitehall, S. K. (2004). The Schizosaccharomyces pombe HIRA-Like Protein Hip1 Is Required for the Periodic Expression of Histone Genes and Contributes to the Function of Complex Centromeres. Mol. Cell. Biol. 24: 4309-4320 [Abstract] [Full Text]  
  • Shiels, B. R., McKellar, S., Katzer, F., Lyons, K., Kinnaird, J., Ward, C., Wastling, J. M., Swan, D. (2004). A Theileria annulata DNA Binding Protein Localized to the Host Cell Nucleus Alters the Phenotype of a Bovine Macrophage Cell Line. Eukaryot Cell 3: 495-505 [Abstract] [Full Text]  
  • Hoek, M., Stillman, B. (2003). Chromatin assembly factor 1 is essential and couples chromatin assembly to DNA replication in vivo. Proc. Natl. Acad. Sci. USA 100: 12183-12188 [Abstract] [Full Text]  
  • Izumiya, Y., Lin, S.-F., Ellison, T. J., Levy, A. M., Mayeur, G. L., Izumiya, C., Kung, H.-J. (2003). Cell Cycle Regulation by Kaposi's Sarcoma-Associated Herpesvirus K-bZIP: Direct Interaction with Cyclin-CDK2 and Induction of G1 Growth Arrest. J. Virol. 77: 9652-9661 [Abstract] [Full Text]  
  • Huang, Y., Kim, S.-O., Jiang, J., Frank, S. J. (2003). Growth Hormone-induced Phosphorylation of Epidermal Growth Factor (EGF) Receptor in 3T3-F442A Cells: MODULATION OF EGF-INDUCED TRAFFICKING AND SIGNALING. J. Biol. Chem. 278: 18902-18913 [Abstract] [Full Text]  
  • Zheng, L., Dominski, Z., Yang, X.-C., Elms, P., Raska, C. S., Borchers, C. H., Marzluff, W. F. (2003). Phosphorylation of Stem-Loop Binding Protein (SLBP) on Two Threonines Triggers Degradation of SLBP, the Sole Cell Cycle-Regulated Factor Required for Regulation of Histone mRNA Processing, at the End of S Phase. Mol. Cell. Biol. 23: 1590-1601 [Abstract] [Full Text]  
  • Nelson, D. M., Ye, X., Hall, C., Santos, H., Ma, T., Kao, G. D., Yen, T. J., Harper, J. W., Adams, P. D. (2002). Coupling of DNA Synthesis and Histone Synthesis in S Phase Independent of Cyclin/cdk2 Activity. Mol. Cell. Biol. 22: 7459-7472 [Abstract] [Full Text]  
  • Khare, L, Astrinidis, A, Senapedis, W, Adams, P D, Henske, E P. (2002). Expression of wild type and mutant TSC2, but not TSC1, causes an increase in the G1 fraction of the cell cycle in HEK293 cells. J. Med. Genet. 39: 676-680 [Full Text]  
  • Roberts, C., Sutherland, H. F., Farmer, H., Kimber, W., Halford, S., Carey, A., Brickman, J. M., Wynshaw-Boris, A., Scambler, P. J. (2002). Targeted Mutagenesis of the Hira Gene Results in Gastrulation Defects and Patterning Abnormalities of Mesoendodermal Derivatives Prior to Early Embryonic Lethality. Mol. Cell. Biol. 22: 2318-2328 [Abstract] [Full Text]  
  • Lee, S., Tarn, C., Wang, W.-H., Chen, S., Hullinger, R. L., Andrisani, O. M. (2002). Hepatitis B Virus X Protein Differentially Regulates Cell Cycle Progression in X-transforming Versus Nontransforming Hepatocyte (AML12) Cell Lines. J. Biol. Chem. 277: 8730-8740 [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»