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 Whitaker, L. L.
Right arrow Articles by Wang, J. Y. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Whitaker, L. L.
Right arrow Articles by Wang, J. Y. J.

 Previous Article  |  Next Article 

Mol Cell Biol, July 1998, p. 4032-4042, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Growth Suppression by an E2F-Binding-Defective Retinoblastoma Protein (RB): Contribution from the RB C Pocketdagger

Laura L. Whitaker, Heyun Su, Rajasekaran Baskaran, Erik S. Knudsen, and Jean Y. J. Wang*

Department of Biology, Center for Molecular Genetics, and Cancer Center, University of California, San Diego, La Jolla, California 92093-0322

Received 14 January 1998/Returned for modification 24 March 1998/Accepted 22 April 1998

Growth suppression by the retinoblastoma protein (RB) is dependent on its ability to form complexes with transcription regulators. At least three distinct protein-binding activities have been identified in RB: the large A/B pocket binds E2F, the A/B pocket binds the LXCXE peptide motif, and the C pocket binds the nuclear c-Abl tyrosine kinase. Substitution of Trp for Arg 661 in the B region of RB (mutant 661) inactivates both E2F and LXCXE binding. The tumor suppression function of mutant 661 is not abolished, because this allele predisposes its carriers to retinoblastoma development with a low penetrance. In cell-based assays, 661 is shown to inhibit G1/S progression. This low-penetrance mutant also induces terminal growth arrest with reduced but detectable activity. We have constructed mutations that disrupt C pocket activity. When overproduced, the RB C-terminal fragment did not induce terminal growth arrest but could inhibit G1/S progression, and this activity was abolished by the C-pocket mutations. In full-length RB, the C-pocket mutations reduced but did not abolish RB function. Interestingly, combination of the C-pocket and 661 mutations completely abolished RB's ability to cause an increase in the percentage of cells in G1 and to induce terminal growth arrest. These results suggest that the A/B or C region can induce a prolongation of G1 through mechanisms that are independent of each other. In contrast, long-term growth arrest requires combined activities from both regions of RB. In addition, E2F and LXCXE binding are not the only mechanisms through which RB inhibits cell growth. The C pocket also contributes to RB-mediated growth suppression.

* Corresponding author. Mailing address: Department of Biology, Bonner Hall 3326, UCSD, 9500 Gilman Dr., La Jolla, CA 92093-0322. Phone: (619) 534-6253. Fax: (619) 534-2821. E-mail: jywang{at}ucsd.edu.

dagger In memory of Laura L. Whitaker, 25 February 1998.

Mol Cell Biol, July 1998, p. 4032-4042, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Esposito, F., Pierantoni, G. M., Battista, S., Melillo, R. M., Scala, S., Chieffi, P., Fedele, M., Fusco, A. (2009). Interaction between HMGA1 and Retinoblastoma Protein Is Required for Adipocyte Differentiation. J. Biol. Chem. 284: 25993-26004 [Abstract] [Full Text]  
  • Marlowe, J. L., Fan, Y., Chang, X., Peng, L., Knudsen, E. S., Xia, Y., Puga, A. (2008). The Aryl Hydrocarbon Receptor Binds to E2F1 and Inhibits E2F1-induced Apoptosis. Mol. Biol. Cell 19: 3263-3271 [Abstract] [Full Text]  
  • Tonnetti, L., Netzel-Arnett, S., Darnell, G. A., Hayes, T., Buzza, M. S., Anglin, I. E., Suhrbier, A., Antalis, T. M. (2008). SerpinB2 Protection of Retinoblastoma Protein from Calpain Enhances Tumor Cell Survival. Cancer Res. 68: 5648-5657 [Abstract] [Full Text]  
  • Huang, X., Masselli, A., Frisch, S. M., Hunton, I. C., Jiang, Y., Wang, J. Y. J. (2007). Blockade of Tumor Necrosis Factor-induced Bid Cleavage by Caspase-resistant Rb. J. Biol. Chem. 282: 29401-29413 [Abstract] [Full Text]  
  • Darnell, G. A., Schroder, W. A., Gardner, J., Harrich, D., Yu, H., Medcalf, R. L., Warrilow, D., Antalis, T. M., Sonza, S., Suhrbier, A. (2006). SerpinB2 Is an Inducible Host Factor Involved in Enhancing HIV-1 Transcription and Replication. J. Biol. Chem. 281: 31348-31358 [Abstract] [Full Text]  
  • Sun, H., Chang, Y., Schweers, B., Dyer, M. A., Zhang, X., Hayward, S. W., Goodrich, D. W. (2006). An E2F Binding-Deficient Rb1 Protein Partially Rescues Developmental Defects Associated with Rb1 Nullizygosity. Mol. Cell. Biol. 26: 1527-1537 [Abstract] [Full Text]  
  • Munakata, T., Nakamura, M., Liang, Y., Li, K., Lemon, S. M. (2005). Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. Proc. Natl. Acad. Sci. USA 102: 18159-18164 [Abstract] [Full Text]  
  • Batsche, E., Desroches, J., Bilodeau, S., Gauthier, Y., Drouin, J. (2005). Rb Enhances p160/SRC Coactivator-dependent Activity of Nuclear Receptors and Hormone Responsiveness. J. Biol. Chem. 280: 19746-19756 [Abstract] [Full Text]  
  • Takahashi, C., Contreras, B., Bronson, R. T., Loda, M., Ewen, M. E. (2004). Genetic Interaction between Rb and K-ras in the Control of Differentiation and Tumor Suppression. Mol. Cell. Biol. 24: 10406-10415 [Abstract] [Full Text]  
  • Marlowe, J. L., Knudsen, E. S., Schwemberger, S., Puga, A. (2004). The Aryl Hydrocarbon Receptor Displaces p300 from E2F-dependent Promoters and Represses S Phase-specific Gene Expression. J. Biol. Chem. 279: 29013-29022 [Abstract] [Full Text]  
  • Darnell, G. A., Antalis, T. M., Johnstone, R. W., Stringer, B. W., Ogbourne, S. M., Harrich, D., Suhrbier, A. (2003). Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif. Mol. Cell. Biol. 23: 6520-6532 [Abstract] [Full Text]  
  • Bowen, C., Birrer, M., Gelmann, E. P. (2002). Retinoblastoma Protein-mediated Apoptosis After gamma -Irradiation. J. Biol. Chem. 277: 44969-44979 [Abstract] [Full Text]  
  • Harbour, J. W. (2001). Molecular Basis of Low-Penetrance Retinoblastoma. Arch Ophthalmol 119: 1699-1704 [Abstract] [Full Text]  
  • Harbour, J. W., Dean, D. C. (2000). The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 14: 2393-2409 [Full Text]  
  • Chen, T.-T., Wang, J. Y. J. (2000). Establishment of Irreversible Growth Arrest in Myogenic Differentiation Requires the RB LXCXE-Binding Function. Mol. Cell. Biol. 20: 5571-5580 [Abstract] [Full Text]  
  • Brantley, M. A. Jr., Harbour, J. W. (2000). Inactivation of Retinoblastoma Protein in Uveal Melanoma by Phosphorylation of Sites in the COOH-Terminal Region. Cancer Res. 60: 4320-4323 [Abstract] [Full Text]  
  • Fajas, L., Paul, C., Zugasti, O., Le Cam, L., Polanowska, J., Fabbrizio, E., Medema, R., Vignais, M.-L., Sardet, C. (2000). pRB binds to and modulates the transrepressing activity of the E1A-regulated transcription factor p120E4F. Proc. Natl. Acad. Sci. USA 10.1073/pnas.130198397v1 [Abstract] [Full Text]  
  • Puga, A., Barnes, S. J., Dalton, T. P., Chang, C.-y., Knudsen, E. S., Maier, M. A. (2000). Aromatic Hydrocarbon Receptor Interaction with the Retinoblastoma Protein Potentiates Repression of E2F-dependent Transcription and Cell Cycle Arrest. J. Biol. Chem. 275: 2943-2950 [Abstract] [Full Text]  
  • Gjoerup, O., Chao, H., DeCaprio, J. A., Roberts, T. M. (2000). pRB-Dependent, J Domain-Independent Function of Simian Virus 40 Large T Antigen in Override of p53 Growth Suppression. J. Virol. 74: 864-874 [Abstract] [Full Text]  
  • Lee, K. Y., Ladha, M. H., McMahon, C., Ewen, M. E. (1999). The Retinoblastoma Protein Is Linked to the Activation of Ras. Mol. Cell. Biol. 19: 7724-7732 [Abstract] [Full Text]  
  • Knudsen, K. E., Fribourg, A. F., Strobeck, M. W., Blanchard, J.-M., Knudsen, E. S. (1999). Cyclin A Is a Functional Target of Retinoblastoma Tumor Suppressor Protein-mediated Cell Cycle Arrest. J. Biol. Chem. 274: 27632-27641 [Abstract] [Full Text]  
  • Kohn, K. W. (1999). Molecular Interaction Map of the Mammalian Cell Cycle Control and DNA Repair Systems. Mol. Biol. Cell 10: 2703-2734 [Abstract] [Full Text]  
  • Fajas, L., Paul, C., Zugasti, O., Le Cam, L., Polanowska, J., Fabbrizio, E., Medema, R., Vignais, M.-L., Sardet, C. (2000). pRB binds to and modulates the transrepressing activity of the E1A-regulated transcription factor p120E4F. Proc. Natl. Acad. Sci. USA 97: 7738-7743 [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»