The Cul3 E3 Ligase Acts as a Tumor Suppressor by Targeting Ubiquitin-Mediated Proteolysis of Distinct Cell Cycle Regulators

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Title
The Cul3 E3 Ligase Acts as a Tumor Suppressor by Targeting Ubiquitin-Mediated Proteolysis of Distinct Cell Cycle Regulators
Contributors
Mesrobian, Cristina M. (creator)
Singer, Jeffrey (director)
Chung, Maureen (reader)
Moss, Steven (reader)
Salazar-Mather, Thais (reader)
Diehl, Alan (reader)
Brown University. Division of Biology and Medicine. Pathobiology (sponsor)
Doi
10.7301/Z0ZK5DXK
Copyright Date
2009
Abstract
Maintenance of an intricate balance between positive and negative regulators of the cell cycle is vital, as altered cell cycle regulation results in the uncontrolled cell division that leads to cancer. Cul3 is a novel type of SCF-like ubiquitin ligase that targets proteins for degradation by the ubiquitin-mediated proteolysis system. Cul3 binds to BTB domain-containing proteins that serve as adaptor molecules, binding the substrate for degradation. A yeast two-hybrid screen for proteins that interact with mammalian Cul3 identified nine BTB domain-containing proteins, called Cullin three binding proteins (Ctbs). More in depth analysis of Ctb9/KLHDC5 has begun to elucidate a role for Cul3 in the regulation of cytoskeletal structure. The work described here shows targeting of the microtubule severing protein, p60/katanin by the Cul3 complex using Ctb9/KLHDC5 as a specific substrate adaptor. Cells that are deficient in Cul3 accumulate excess p60/katanin, and are unable to complete mitosis normally, resulting in the accumulation of binucleated cells. This work represents a novel way in which Cul3 activity regulates the cell cycle by controlling microtubule dynamics during mitosis. A major substrate of Cul3 is cyclin E. Elevated levels of cyclin E protein have been detected in breast cancers, and such increased expression is correlated with a poorer prognosis. However, cell lines derived from human breast tumors rarely show increased cyclin E mRNA levels, implying the changes are occurring posttranscriptionally. We hypothesized that altered Cul3 activity may be responsible for the accumulation of cyclin E. The work presented in this thesis describes the development of a model system to determine the role Cul3 plays in breast cancer. Targeted deletion of Cul3 from mouse mammary tissue results in hyperplasia of the mammary ducts and increased cyclin E protein levels in the tissue. These conditions are extremely likely to lead to a malignant state. Based on this work and the work of others, we propose that Cul3 acts as a tumor suppressor by targeting for degradation multiple proteins involved in cell cycle regulation.
Keywords
tumor suppressor
Cell cycle
Ubiquitin
Proteolysis
Notes
Thesis (Ph.D.) -- Brown University (2009)
Extent
xvi, 249 p.

Citation

Mesrobian, Cristina M., "The Cul3 E3 Ligase Acts as a Tumor Suppressor by Targeting Ubiquitin-Mediated Proteolysis of Distinct Cell Cycle Regulators" (2009). Biology and Medicine Theses and Dissertations, Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z0ZK5DXK

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