This Article
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 Diehl, J. A.
Right arrow Articles by Sherr, C. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Diehl, J. A.
Right arrow Articles by Sherr, C. J.

 Previous Article  |  Next Article 

Mol. Cell. Biol., 12 1997, 7362-7374, Vol 17, No. 12
Copyright © 1997, American Society for Microbiology

A dominant-negative cyclin D1 mutant prevents nuclear import of cyclin- dependent kinase 4 (CDK4) and its phosphorylation by CDK-activating kinase

JA Diehl and CJ Sherr
Howard Hughes Medical Institute, Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Cyclins contain two characteristic cyclin folds, each consisting of five alpha-helical bundles, which are connected to one another by a short linker peptide. The first repeat makes direct contact with cyclin- dependent kinase (CDK) subunits in assembled holoenzyme complexes, whereas the second does not contribute directly to the CDK interface. Although threonine 156 in mouse cyclin D1 is predicted to lie at the carboxyl terminus of the linker peptide that separates the two cyclin folds and is buried within the cyclin subunit, mutation of this residue to alanine has profound effects on the behavior of the derived cyclin D1-CDK4 complexes. CDK4 in complexes with mutant cyclin D1 (T156A or T156E but not T156S) is not phosphorylated by recombinant CDK- activating kinase (CAK) in vitro, fails to undergo activating T-loop phosphorylation in vivo, and remains catalytically inactive and unable to phosphorylate the retinoblastoma protein. Moreover, when it is ectopically overexpressed in mammalian cells, cyclin D1 (T156A) assembles with CDK4 in the cytoplasm but is not imported into the cell nucleus. CAK phosphorylation is not required for nuclear transport of cyclin D1-CDK4 complexes, because complexes containing wild-type cyclin D1 and a CDK4 (T172A) mutant lacking the CAK phosphorylation site are efficiently imported. In contrast, enforced overexpression of the CDK inhibitor p21Cip1 together with mutant cyclin D1 (T156A)-CDK4 complexes enhanced their nuclear localization. These results suggest that cyclin D1 (T156A or T156E) forms abortive complexes with CDK4 that prevent recognition by CAK and by other cellular factors that are required for their nuclear localization. These properties enable ectopically overexpressed cyclin D1 (T156A), or a more stable T156A/T286A double mutant that is resistant to ubiquitination, to compete with endogenous cyclin D1 in mammalian cells, thereby mobilizing CDK4 into cytoplasmic, catalytically inactive complexes and dominantly inhibiting the ability of transfected NIH 3T3 fibroblasts to enter S phase.


This article has been cited by other articles:

  • He, L. M., Sartori, D. J., Teta, M., Opare-Addo, L. M., Rankin, M. M., Long, S. Y., Diehl, J. A., Kushner, J. A. (2009). Cyclin D2 Protein Stability Is Regulated in Pancreatic {beta}-Cells. Mol. Endocrinol. 23: 1865-1875 [Abstract] [Full Text]  
  • Bockstaele, L., Bisteau, X., Paternot, S., Roger, P. P. (2009). Differential Regulation of Cyclin-Dependent Kinase 4 (CDK4) and CDK6, Evidence that CDK4 Might Not Be Activated by CDK7, and Design of a CDK6 Activating Mutation. Mol. Cell. Biol. 29: 4188-4200 [Abstract] [Full Text]  
  • Jadlowsky, J. K., Nojima, M., Okamoto, T., Fujinaga, K. (2008). Dominant negative mutant cyclin T1 proteins that inhibit HIV transcription by forming a kinase inactive complex with Tat. J. Gen. Virol. 89: 2783-2787 [Abstract] [Full Text]  
  • Piscopo, D. M., Hinds, P. W. (2008). A Role for the Cyclin Box in the Ubiquitin-Mediated Degradation of Cyclin G1. Cancer Res. 68: 5581-5590 [Abstract] [Full Text]  
  • Menges, M., Pavesi, G., Morandini, P., Bogre, L., Murray, J. A.H. (2007). Genomic Organization and Evolutionary Conservation of Plant D-Type Cyclins. Plant Physiol. 145: 1558-1576 [Abstract] [Full Text]  
  • Chan, W. M., Poon, R. Y.C. (2007). The p53 Isoform {Delta}p53 Lacks Intrinsic Transcriptional Activity and Reveals the Critical Role of Nuclear Import in Dominant-Negative Activity. Cancer Res. 67: 1959-1969 [Abstract] [Full Text]  
  • Wang, J.-g., Barsky, L. W., Davicioni, E., Weinberg, K. I., Triche, T. J., Zhang, X.-k., Wu, L. (2006). Retinoic acid induces leukemia cell G1 arrest and transition into differentiation by inhibiting cyclin-dependent kinase-activating kinase binding and phosphorylation of PML/RAR{alpha}. FASEB J. 20: 2142-2144 [Abstract] [Full Text]  
  • Bockstaele, L., Kooken, H., Libert, F., Paternot, S., Dumont, J. E., de Launoit, Y., Roger, P. P., Coulonval, K. (2006). Regulated Activating Thr172 Phosphorylation of Cyclin-Dependent Kinase 4(CDK4): Its Relationship with Cyclins and CDK "Inhibitors".. Mol. Cell. Biol. 26: 5070-5085 [Abstract] [Full Text]  
  • Menges, M., Samland, A. K., Planchais, S., Murray, J. A.H. (2006). The D-Type Cyclin CYCD3;1 Is Limiting for the G1-to-S-Phase Transition in Arabidopsis. Plant Cell 18: 893-906 [Abstract] [Full Text]  
  • Kwak, Y.-T., Li, R., Becerra, C. R., Tripathy, D., Frenkel, E. P., Verma, U. N. (2005). I{kappa}B Kinase {alpha} Regulates Subcellular Distribution and Turnover of Cyclin D1 by Phosphorylation. J. Biol. Chem. 280: 33945-33952 [Abstract] [Full Text]  
  • Chen, B., Pan, H., Zhu, L., Deng, Y., Pollard, J. W. (2005). Progesterone Inhibits the Estrogen-Induced Phosphoinositide 3-Kinase->AKT->GSK-3{beta}->Cyclin D1->pRB Pathway to Block Uterine Epithelial Cell Proliferation. Mol. Endocrinol. 19: 1978-1990 [Abstract] [Full Text]  
  • Tapinos, N., Rambukkana, A. (2005). Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli. Proc. Natl. Acad. Sci. USA 102: 9188-9193 [Abstract] [Full Text]  
  • Arnold, A., Papanikolaou, A. (2005). Cyclin D1 in Breast Cancer Pathogenesis. JCO 23: 4215-4224 [Abstract] [Full Text]  
  • Kaldis, P. (2005). The N-terminal Peptide of the Kaposi's Sarcoma-associated Herpesvirus (KSHV)-cyclin Determines Substrate Specificity. J. Biol. Chem. 280: 11165-11174 [Abstract] [Full Text]  
  • Pasumarthi, K. B.S., Nakajima, H., Nakajima, H. O., Soonpaa, M. H., Field, L. J. (2005). Targeted Expression of Cyclin D2 Results in Cardiomyocyte DNA Synthesis and Infarct Regression in Transgenic Mice. Circ. Res. 96: 110-118 [Abstract] [Full Text]  
  • Zou, Y., Ewton, D. Z., Deng, X., Mercer, S. E., Friedman, E. (2004). Mirk/dyrk1B Kinase Destabilizes Cyclin D1 by Phosphorylation at Threonine 288. J. Biol. Chem. 279: 27790-27798 [Abstract] [Full Text]  
  • Yang, P., Roy, S. K. (2004). Follicle Stimulating Hormone-Induced DNA Synthesis in the Granulosa Cells of Hamster Preantral Follicles Involves Activation of Cyclin-Dependent Kinase-4 Rather Than Cyclin D2 Synthesis. Biol. Reprod. 70: 509-517 [Abstract] [Full Text]  
  • Paternot, S., Coulonval, K., Dumont, J. E., Roger, P. P. (2003). Cyclic AMP-dependent Phosphorylation of Cyclin D3-bound CDK4 Determines the Passage through the Cell Cycle Restriction Point in Thyroid Epithelial Cells. J. Biol. Chem. 278: 26533-26540 [Abstract] [Full Text]  
  • Ericson, K. K., Krull, D., Slomiany, P., Grossel, M. J. (2003). Expression of Cyclin-Dependent Kinase 6, but not Cyclin-Dependent Kinase 4, Alters Morphology of Cultured Mouse Astrocytes. Mol Cancer Res 1: 654-664 [Abstract] [Full Text]  
  • Chen, B., Pollard, J. W. (2003). Cyclin D2 Compensates for the Loss of Cyclin D1 in Estrogen-Induced Mouse Uterine Epithelial Cell Proliferation. Mol. Endocrinol. 17: 1368-1381 [Abstract] [Full Text]  
  • Ratschiller, D., Heighway, J., Gugger, M., Kappeler, A., Pirnia, F., Schmid, R.A., Borner, M.M., Betticher, D.C. (2003). Cyclin D1 Overexpression in Bronchial Epithelia of Patients With Lung Cancer Is Associated With Smoking and Predicts Survival. JCO 21: 2085-2093 [Abstract] [Full Text]  
  • Diehl, J. A., Yang, W., Rimerman, R. A., Xiao, H., Emili, A. (2003). Hsc70 Regulates Accumulation of Cyclin D1 and Cyclin D1-Dependent Protein Kinase. Mol. Cell. Biol. 23: 1764-1774 [Abstract] [Full Text]  
  • Santamaria, A., Fernandez, P. L., Farre, X., Benedit, P., Reventos, J., Morote, J., Paciucci, R., Thomson, T. M. (2003). PTOV-1, a Novel Protein Overexpressed in Prostate Cancer, Shuttles between the Cytoplasm and the Nucleus and Promotes Entry into the S Phase of the Cell Division Cycle. Am. J. Pathol. 162: 897-905 [Abstract] [Full Text]  
  • Wang, J., Barsky, L. W., Shum, C. H., Jong, A., Weinberg, K. I., Collins, S. J., Triche, T. J., Wu, L. (2002). Retinoid-induced G1 Arrest and Differentiation Activation Are Associated with a Switch to Cyclin-dependent Kinase-activating Kinase Hypophosphorylation of Retinoic Acid Receptor alpha. J. Biol. Chem. 277: 43369-43376 [Abstract] [Full Text]  
  • Nakagami, H., Kawamura, K., Sugisaka, K., Sekine, M., Shinmyo, A. (2002). Phosphorylation of Retinoblastoma-Related Protein by the Cyclin D/Cyclin-Dependent Kinase Complex Is Activated at the G1/S-Phase Transition in Tobacco. Plant Cell 14: 1847-1857 [Abstract] [Full Text]  
  • Wu, K., Wang, C., D'Amico, M., Lee, R. J., Albanese, C., Pestell, R. G., Mani, S. (2002). Flavopiridol and Trastuzumab Synergistically Inhibit Proliferation of Breast Cancer Cells: Association with Selective Cooperative Inhibition of Cyclin D1-dependent Kinase and Akt Signaling Pathways. Molecular Cancer Therapeutics 1: 695-706 [Abstract] [Full Text]  
  • Hlaing, M., Shen, X., Dazin, P., Bernstein, H. S. (2002). The Hypertrophic Response in C2C12 Myoblasts Recruits the G1 Cell Cycle Machinery. J. Biol. Chem. 277: 23794-23799 [Abstract] [Full Text]  
  • Alt, J. R., Gladden, A. B., Diehl, J. A. (2002). p21Cip1 Promotes Cyclin D1 Nuclear Accumulation via Direct Inhibition of Nuclear Export. J. Biol. Chem. 277: 8517-8523 [Abstract] [Full Text]  
  • Jackman, M., Kubota, Y., den Elzen, N., Hagting, A., Pines, J. (2002). Cyclin A- and Cyclin E-Cdk Complexes Shuttle between the Nucleus and the Cytoplasm. Mol. Biol. Cell 13: 1030-1045 [Abstract] [Full Text]  
  • Skildum, A. J., Mukherjee, S., Conrad, S. E. (2002). The Cyclin-dependent Kinase Inhibitor p21WAF1/Cip1 Is an Antiestrogen-regulated Inhibitor of Cdk4 in Human Breast Cancer Cells. J. Biol. Chem. 277: 5145-5152 [Abstract] [Full Text]  
  • Megason, S. G., McMahon, A. P. (2002). A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. Development 129: 2087-2098 [Abstract] [Full Text]  
  • Dolci, S., Pellegrini, M., Di Agostino, S., Geremia, R., Rossi, P. (2001). Signaling through Extracellular Signal-regulated Kinase Is Required for Spermatogonial Proliferative Response to Stem Cell Factor. J. Biol. Chem. 276: 40225-40233 [Abstract] [Full Text]  
  • Hu, G., Lee, H., Price, S. M., Shen, M. M., Abate-Shen, C. (2001). Msx homeobox genes inhibit differentiation through upregulation of cyclin D1. Development 128: 2373-2384 [Abstract] [Full Text]  
  • Miller, M., Cross, F. (2001). Cyclin specificity: how many wheels do you need on a unicycle?. J. Cell Sci. 114: 1811-1820 [Abstract]  
  • Wu, L., Chen, P., Shum, C. H., Chen, C., Barsky, L. W., Weinberg, K. I., Jong, A., Triche, T. J. (2001). MAT1-Modulated CAK Activity Regulates Cell Cycle G1 Exit. Mol. Cell. Biol. 21: 260-270 [Abstract] [Full Text]  
  • Alt, J. R., Cleveland, J. L., Hannink, M., Diehl, J. A. (2000). Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev. 14: 3102-3114 [Abstract] [Full Text]  
  • Brewer, J. W., Diehl, J. A. (2000). PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc. Natl. Acad. Sci. USA 10.1073/pnas.220247197v1 [Abstract] [Full Text]  
  • Lin, X., Nelson, P., Gelman, I. H. (2000). SSeCKS, a Major Protein Kinase C Substrate with Tumor Suppressor Activity, Regulates G1right-arrowS Progression by Controlling the Expression and Cellular Compartmentalization of Cyclin D. Mol. Cell. Biol. 20: 7259-7272 [Abstract] [Full Text]  
  • Francesconi, C. M., Hutcheon, A. E. K., Chung, E.-H., Dalbone, A. C., Joyce, N. C., Zieske, J. D. (2000). Expression Patterns of Retinoblastoma and E2F Family Proteins during Corneal Development. IOVS 41: 1054-1062 [Abstract] [Full Text]  
  • Depoortere, F., Pirson, I., Bartek, J., Dumont, J. E., Roger, P. P. (2000). Transforming Growth Factor beta 1 Selectively Inhibits the Cyclic AMP-dependent Proliferation of Primary Thyroid Epithelial Cells by Preventing the Association of Cyclin D3-cdk4 with Nuclear p27kip1. Mol. Biol. Cell 11: 1061-1076 [Abstract] [Full Text]  
  • Miller, M. E., Cross, F. R. (2000). Distinct Subcellular Localization Patterns Contribute to Functional Specificity of the Cln2 and Cln3 Cyclins of Saccharomyces cerevisiae. Mol. Cell. Biol. 20: 542-555 [Abstract] [Full Text]  
  • Lee, R. J., Albanese, C., Fu, M., D'Amico, M., Lin, B., Watanabe, G., Haines, G. K. III, Siegel, P. M., Hung, M.-C., Yarden, Y., Horowitz, J. M., Muller, W. J., Pestell, R. G. (2000). Cyclin D1 Is Required for Transformation by Activated Neu and Is Induced through an E2F-Dependent Signaling Pathway. Mol. Cell. Biol. 20: 672-683 [Abstract] [Full Text]  
  • Harvey, K. J., Lukovic, D., Ucker, D. S. (2000). Caspase-Dependent Cdk Activity Is a Requisite Effector of Apoptotic Death Events. JCB 148: 59-72 [Abstract] [Full Text]  
  • Albrecht, J. H., Rieland, B. M., Nelsen, C. J., Ahonen, C. L. (1999). Regulation of G1 cyclin-dependent kinases in the liver: role of nuclear localization and p27 sequestration. Am. J. Physiol. Gastrointest. Liver Physiol. 277: G1207-G1216 [Abstract] [Full Text]  
  • Ashton, A. W., Watanabe, G., Albanese, C., Harrington, E. O., Ware, J. A., Pestell, R. G. (1999). Protein Kinase Cdelta Inhibition of S-Phase Transition in Capillary Endothelial Cells Involves the Cyclin-dependent Kinase Inhibitor p27Kip1. J. Biol. Chem. 274: 20805-20811 [Abstract] [Full Text]  
  • Tong, W., Pollard, J. W. (1999). Progesterone Inhibits Estrogen-Induced Cyclin D1 and cdk4 Nuclear Translocation, Cyclin E- and Cyclin A-cdk2 Kinase Activation, and Cell Proliferation in Uterine Epithelial Cells in Mice. Mol. Cell. Biol. 19: 2251-2264 [Abstract] [Full Text]  
  • Moore, J. D., Yang, J., Truant, R., Kornbluth, S. (1999). Nuclear Import of Cdk/Cyclin Complexes: Identification of Distinct Mechanisms for Import of Cdk2/Cyclin E and Cdc2/Cyclin B1. JCB 144: 213-224 [Abstract] [Full Text]  
  • Taules, M., Rius, E., Talaya, D., Lopez-Girona, A., Bachs, O., Agell, N. (1998). Calmodulin Is Essential for Cyclin-dependent Kinase 4 (Cdk4) Activity and Nuclear Accumulation of Cyclin D1-Cdk4 during G1. J. Biol. Chem. 273: 33279-33286 [Abstract] [Full Text]  
  • Diehl, J. A., Cheng, M., Roussel, M. F., Sherr, C. J. (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12: 3499-3511 [Abstract] [Full Text]  
  • Park, D. S., Morris, E. J., Padmanabhan, J., Shelanski, M. L., Geller, H. M., Greene, L. A. (1998). Cyclin-dependent Kinases Participate in Death of Neurons Evoked by DNA-damaging Agents. JCB 143: 457-467 [Abstract] [Full Text]  
  • Kaldis, P., Russo, A. A., Chou, H. S., Pavletich, N. P., Solomon, M. J. (1998). Human and Yeast Cdk-activating Kinases (CAKs) Display Distinct Substrate Specificities. Mol. Biol. Cell 9: 2545-2560 [Abstract] [Full Text]  
  • Casanovas, O., Miro, F., Estanyol, J. M., Itarte, E., Agell, N., Bachs, O. (2000). Osmotic Stress Regulates the Stability of Cyclin D1 in a p38SAPK2-dependent Manner. J. Biol. Chem. 275: 35091-35097 [Abstract] [Full Text]  
  • Chu, C., Kohtz, D. S. (2001). Identification of the E2A Gene Products as Regulatory Targets of the G1 Cyclin-dependent Kinases. J. Biol. Chem. 276: 8524-8534 [Abstract] [Full Text]  
  • Healy, J. M. S., Menges, M., Doonan, J. H., Murray, J. A. H. (2001). The Arabidopsis D-type Cyclins CycD2 and CycD3 Both Interact in Vivo with the PSTAIRE Cyclin-dependent Kinase Cdc2a but Are Differentially Controlled. J. Biol. Chem. 276: 7041-7047 [Abstract] [Full Text]  
  • Rimerman, R. A., Gellert-Randleman, A., Diehl, J. A. (2000). Wnt1 and MEK1 Cooperate to Promote Cyclin D1 Accumulation and Cellular Transformation. J. Biol. Chem. 275: 14736-14742 [Abstract] [Full Text]  
  • Brewer, J. W., Diehl, J. A. (2000). PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc. Natl. Acad. Sci. USA 97: 12625-12630 [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»