Role of the Acetyltransferase p300 in Cellular Responses

Summary

Principal Investigator: Maria Avantaggiati
Abstract: Drugs that affects the microtubule dynamics constitute one of the most important classes of chemotherapeutic agents. Anti-microtubule drugs of clinical relevance include paclitaxel (taxol), vinca alkaloids (vinblastin and vincrisitn), nocodazole and colchicine. These agents trigger a checkpoint, the spindle checkpoint, which monitors he attachment of chromosomes to the spindle, and elicits arrest in mitosis generally followed by apoptosis. Several cellular factors which participate in this checkpoint have recently been identified, however, the exact molecular mechanisms through which errors in spindle assembly, or chromosomes attachment to the spindle engage the cell cycle machinery remain to be elucidated. We made the novel finding that a transcription coactivator possessing acetyltransferase activity, p300, enhances the mitotic arrest elicited by taxol. Acetyltransferases belonging to the p300 family have been implicated in conveying adaptive responses in a variety of signal transduction pathways, through regulation of transcription of many cell-cycle regulatory genes. We now demonstrate that p300 associates with mitotic and interphase microtubules, it acetylates tubulin, and it favors tubulin polymerization in a taxol-dependent assay. Moreover p300 levels and its association with microtubules are significantly increased in taxol treated cells. Based on these results we hypothesize that p300 acts as an important effector of sensitivity of tumor cells to taxol, through its association with tubulin and through its activity as a transcription factor. To test this hypothesis we will: l)Identify the regions of p300 responsible for its interaction with microtubules and generate mutants with corrupted tubulin-binding ability (loss or gain of function, respectively). 2) Study how these mutants influence cytoskeleton architecture, spindle assembly and nuclear import of acetylated transcription factors in taxol treated cells. 3)Define the mechanisms by which p300 participates in cell cycle arrest and apoptosis induced by taxol and identify the molecular events occurring downstream of taxol which are influenced by p300. 4)Provide a rationale and a strategy for the design of molecules, such as peptides which mimics p300 effects on apoptosis, able to enhance chemosensitivity to taxol. Since mitotic spindle inhibitors constitute a growing class of anti-cancer agents, it is essential to understand molecular mechanisms of resistance and sensitivity. Thus, studies proposed in this application are expected to have important clinical implications.
Funding Period: 2002-08-06 - 2008-07-31
more information: NIH RePORT

Top Publications

  1. pmc An intrinsically disordered region of the acetyltransferase p300 with similarity to prion-like domains plays a role in aggregation
    Alexander Kirilyuk
    Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, District of Columbia, United States of America
    PLoS ONE 7:e48243. 2012
  2. pmc Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate
    Chad D Knights
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
    J Cell Biol 173:533-44. 2006
  3. pmc The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration
    Simone Di Giovanni
    Laboratory for NeuroRegeneration and Repair, Hertie Institute for Clinical Brain Research, University of Tuebingen, Germany
    EMBO J 25:4084-96. 2006

Scientific Experts

  • Maria Avantaggiati
  • Simone Di Giovanni
  • Alexander Kirilyuk
  • Jason Catania
  • Chad D Knights
  • Vladimir N Uversky
  • Christopher Albanese
  • Geetaram Sahu
  • Jeffrey A Toretsky
  • Nagarajan Pattabiraman
  • Mika Shimoji
  • Antonio Giordano
  • Italo Mocchetti
  • Ricardo Perez
  • Xiaojing Zhang
  • Richard G Pestell
  • Selen Muratoglu
  • Andrew A Quong
  • Terry Beerman
  • Amber Swartzbeck

Detail Information

Publications3

  1. pmc An intrinsically disordered region of the acetyltransferase p300 with similarity to prion-like domains plays a role in aggregation
    Alexander Kirilyuk
    Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, District of Columbia, United States of America
    PLoS ONE 7:e48243. 2012
    ..These data unravel a novel activity of p300, offer new insights into the function of disordered domains and implicate p300 in pathological aggregation that occurs in neurodegeneration and cancer...
  2. pmc Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate
    Chad D Knights
    Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
    J Cell Biol 173:533-44. 2006
    ....
  3. pmc The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration
    Simone Di Giovanni
    Laboratory for NeuroRegeneration and Repair, Hertie Institute for Clinical Brain Research, University of Tuebingen, Germany
    EMBO J 25:4084-96. 2006
    ..These observations may suggest a novel therapeutic target for promoting regenerative responses following peripheral or central nervous system injuries...