Evaluating downstream targets of cullin4-dependent E3 ligases and of D-type cyclins: implications for the dysregulation of ubiquitination and cell growth in cancer Public Deposited

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  • March 21, 2019
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  • Zacharek, Sima
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Cyclin D1 and cullin4 (CUL4) are two proteins known to be upregulated in cancer. Cyclin D1 functions to regulate the cell division cycle and cell growth, while CUL4 assembles E3 ubiquitin ligase complexes that function to ubiquitinate target proteins, often marking them for degradation. However, the downstream effectors of their oncogenic activities are not fully characterized. Therefore, the aim of this study was to discover novel targets of the D-type cyclins and of CUL4, and to better describe the E3 ubiquitin ligase complexes assembled by CUL4. We identified the TSC1- TSC2 tumor suppressor complex, a key negative regulator of cell growth, as a cyclin D-interacting complex, and demonstrated that D-type cyclins could down-regulate the activity of TSC1-TSC2 by both CDK (Cyclin Dependent Kinase) -dependent and -independent mechanisms. In a separate line of studies, I conducted a genetic analysis of mutants of Cul4 and one of its putative substrate receptor molecules, Ddb1 (Damaged DNA Binding protein 1) in Drosophila, and established that CUL4DDB1 plays an essential role in cell growth, proliferation, and development. These studies suggested a number of novel substrates of the CUL4DDB1 ligase, and also served to clarify the role of CUL4DDB1 in controlling the degradation of the replication licensing factor CDT1/DUP during the cell cycle. Collectively, these analyses of the D-type cyclins and CUL4 broaden our understanding of the consequence of their disruption in cancer development.
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  • Xiong, Yue
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