Regulation of the cell cycle and signaling by CUL-2 E3 complexes

Summary

Principal Investigator: Edward T Kipreos
Abstract: DESCRIPTION (provided by applicant): Cullin 2-RING ubiquitin ligase (CRL2) complexes target proteins for degradation to control dynamic cellular processes including the cell cycle, polarity, and signal transduction. This proposal focuses on understanding the molecular pathways that regulate how CRL2 complexes control: the actin cytoskeleton and cell motility;the Ras and Notch signaling pathways;and the mitotic regulator cyclin B. These CRL2-regulated pathways have important implications for the control of cell proliferation, development, and cancer. Aim 1 focuses on CRL2-mediated regulation of the CDK-inhibitors p21Cip1 and p27Kip2 in the cytoplasm. CRL2LRR1 targets the degradation of cytoplasmic p21 to control actin cytoskeletal dynamics and cell motility. Proposed experiments address the regulation of p21 binding to CRL2LRR1, and the mechanism by which certain oncogenes circumvent CRL2LRR1-mediated degradation of p21. A distinct CRL2 complex regulates cytoplasmic p27 levels through an indirect mechanism by negatively regulating the levels of the Ras pathway effectors RSK1 and RSK2. Experiments address how the degradation of RSK1/2 is regulated;the functional consequences of the degradation;and the identification of the substrate-recognition subunit for the CRL2 complex. Aim 2 seeks to identify the molecular pathway by which CRL2LRR-1 represses Notch signaling in the developing C. elegans vulva, through the use of genetic analysis in combination with reporter transgenes. Aim 3 focuses on the paradigm-shifting observation that the mitotic regulator cyclin B is targeted for degradation not only by the APC/C complex (which is currently regarded as the sole ubiquitin ligase for cyclin B degradation) but also by the CRL2ZYG-11 complex. The cyclin B-CDK1 complex is the key cell cycle regulator that drives cells into mitosis;and the degradation of cyclin B is essential for mitotic exit. Discovering how the degradation of cyclin B is regulated is critical for understandin the overall regulation of mitosis. The experiments in this aim will characterize the interaction of cyclin B with CRL2ZYG-11, determine the mechanism through which the degradation is cell cycle regulated, and explore whether the pathway is conserved in mammals.
Funding Period: 2007-02-01 - 2016-03-31
more information: NIH RePORT

Top Publications

  1. pmc A CUL-2 ubiquitin ligase containing three FEM proteins degrades TRA-1 to regulate C. elegans sex determination
    Natalia G Starostina
    Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
    Dev Cell 13:127-39. 2007
  2. ncbi Control of the Cdc6 replication licensing factor in metazoa: the role of nuclear export and the CUL4 ubiquitin ligase
    Jihyun Kim
    Department of Cellular Biology, University of Georgia, Athens, Georgia 30606 2607, USA
    Cell Cycle 7:146-50. 2008
  3. pmc The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing
    Youngjo Kim
    Department of Cellular Biology, University of Georgia, Athens, Georgia 30602 USA
    Genes Dev 22:2507-19. 2008
  4. pmc Wnt/beta-catenin signaling: components, mechanisms, and diseases
    Bryan T MacDonald
    F M Kirby Neurobiology Center, Children s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
    Dev Cell 17:9-26. 2009
  5. pmc C. elegans CAND-1 regulates cullin neddylation, cell proliferation and morphogenesis in specific tissues
    Dimple R Bosu
    Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
    Dev Biol 346:113-26. 2010
  6. pmc MEC-17 is an alpha-tubulin acetyltransferase
    Jyothi S Akella
    Department of Cellular Biology, University of Georgia, Athens, Georgia 30602, USA
    Nature 467:218-22. 2010
  7. pmc CRL2(LRR-1) targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human cells
    Natalia G Starostina
    Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
    Dev Cell 19:753-64. 2010
  8. pmc Overcoming redundancy: an RNAi enhancer screen for morphogenesis genes in Caenorhabditis elegans
    Jacob M Sawyer
    Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    Genetics 188:549-64. 2011
  9. pmc Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors
    Natalia G Starostina
    Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
    Trends Cell Biol 22:33-41. 2012

Research Grants

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  2. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
  3. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
  4. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
  5. Mechanisms of Nuclear and Cell Fusion in Yeast
    MARK DAVID ROSE; Fiscal Year: 2013
  6. Effects of the PI3K Pathway on p27 Function and Cancer Progression
    JOYCE MARIE SLINGERLAND; Fiscal Year: 2013
  7. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  8. Interrogating Epigenetic Changes in Cancer Genomes
    Tim H M Huang; Fiscal Year: 2013
  9. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
  10. CSHL CANCER CENTER SUPPORT GRANT
    BRUCE W STILLMAN; Fiscal Year: 2013

Detail Information

Publications9

  1. pmc A CUL-2 ubiquitin ligase containing three FEM proteins degrades TRA-1 to regulate C. elegans sex determination
    Natalia G Starostina
    Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
    Dev Cell 13:127-39. 2007
    ..This work demonstrates that the terminal step in C. elegans sex determination is controlled by ubiquitin-mediated proteolysis...
  2. ncbi Control of the Cdc6 replication licensing factor in metazoa: the role of nuclear export and the CUL4 ubiquitin ligase
    Jihyun Kim
    Department of Cellular Biology, University of Georgia, Athens, Georgia 30606 2607, USA
    Cell Cycle 7:146-50. 2008
    ..This work also identifies the CUL-4 ubiquitin ligase as a master regulator that controls DNA replication by regulating both Cdt1 and Cdc6 replication licensing factors...
  3. pmc The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing
    Youngjo Kim
    Department of Cellular Biology, University of Georgia, Athens, Georgia 30602 USA
    Genes Dev 22:2507-19. 2008
    ..Our work defines the degradation of p21 as a critical aspect of replication licensing in human cells...
  4. pmc Wnt/beta-catenin signaling: components, mechanisms, and diseases
    Bryan T MacDonald
    F M Kirby Neurobiology Center, Children s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
    Dev Cell 17:9-26. 2009
    ..Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications...
  5. pmc C. elegans CAND-1 regulates cullin neddylation, cell proliferation and morphogenesis in specific tissues
    Dimple R Bosu
    Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
    Dev Biol 346:113-26. 2010
    ....
  6. pmc MEC-17 is an alpha-tubulin acetyltransferase
    Jyothi S Akella
    Department of Cellular Biology, University of Georgia, Athens, Georgia 30602, USA
    Nature 467:218-22. 2010
    ..In summary, we identify MEC-17 as an enzyme that acetylates the K40 residue of alpha-tubulin, the only PTM known to occur on the luminal surface of microtubules...
  7. pmc CRL2(LRR-1) targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human cells
    Natalia G Starostina
    Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
    Dev Cell 19:753-64. 2010
    ..Inactivation of human CRL2(LRR1) leads to the activation of the actin-depolymerizing protein cofilin, dramatic reorganization of the actin cytoskeleton, and increased cell motility...
  8. pmc Overcoming redundancy: an RNAi enhancer screen for morphogenesis genes in Caenorhabditis elegans
    Jacob M Sawyer
    Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    Genetics 188:549-64. 2011
    ..Our results implicate new genes in C. elegans gastrulation, and they show that an RNAi-based enhancer screen in C. elegans can be used as an efficient means to identify important but redundant or partially redundant developmental genes...
  9. pmc Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors
    Natalia G Starostina
    Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA
    Trends Cell Biol 22:33-41. 2012
    ..This review analyzes recent data highlighting our current understanding of how distinct E3 pathways regulate subpopulations of the CKIs to control their diverse functions...

Research Grants30

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  2. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  3. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  4. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  5. Mechanisms of Nuclear and Cell Fusion in Yeast
    MARK DAVID ROSE; Fiscal Year: 2013
    ..We will use advanced imaging and genetic methods to identify Kar5p's role(s) in nuclear membrane fusion. ..
  6. Effects of the PI3K Pathway on p27 Function and Cancer Progression
    JOYCE MARIE SLINGERLAND; Fiscal Year: 2013
    ....
  7. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  8. Interrogating Epigenetic Changes in Cancer Genomes
    Tim H M Huang; Fiscal Year: 2013
    ..abstract_text> ..
  9. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  10. CSHL CANCER CENTER SUPPORT GRANT
    BRUCE W STILLMAN; Fiscal Year: 2013
    ....
  11. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....