Ubiquitin and cell cycle control
The ubiquitin proteasome system plays an essential role in normal proliferation and cell cycle progression. In addition, dysfunctional ubiquitin signaling contributes to cancer.
Our goal is to determine mechanisms by which the ubiquitin pathway promotes normal cell cycle progression and proliferation, and to examine how dysfunction in these pathways promotes tumor cell proliferation.
The cancer cell cycle
The G1/S boundary represents a major barrier to tumorigenesis. We recently identified a double negative feedback loop, involving two E3 ubiquitin ligases, that controls S-phase entry (Choudhury et al, 2016). Significantly, we showed that this circuit is controlled by the oncogenic kinase AKT (Choudhury et al, 2017). We are investigating additional substrates controlled by these two E3 enzymes, and the mechanisms by which they promote normal and cancer cell cycles.
Cell cycle transcription
The ubiquitin system plays a vital role in shaping transcriptional dynamics. We are specifically interested in a cell cycle transcription factor FoxM1, that is hyper-activated in several malignancies, including high-grade serous ovarian cancers and triple-negative, basal-like breast cancer. We recently discovered a component in the ubiquitin system that, paradoxically, promotes FoxM1 degradation and activation (Wang et al, 2016). In addition, we discovered that an ezyme termed USP21, which is recurrently upregulated in breast cancer, increases FoxM1 by blocking its degradation (Arceci et al, 2019). We are focused on mechanisms by which FoxM1 is regulated and in defining strategies to attack FoxM1 for therapeutic benefit.
deubiquitinases in cell cycle
Like other post-translational modifications, ubiquitin is reversible and is removed from substrates by catalytic proteases termed deubiquitinases or DUBs. We are examining the role of DUBs is in cell cycle progression and transitions, substrate degradation and genome integrity. We recently described Cezanne/OTUD7B as a new cell cycle DUB that antagonizes the APC/C ubiquitin ligase at the exit from mitosis (Bonacci et al, EMBO Journal, 2018). In addition, we also found that DUBs promote the transcription of key mitotic genes by regulating the oncogenic, cell cycle transcription factor FoxM1 (Arceci et al, 2019).
Chromosome segregation fidelity during mitosis is essential to prevent chromosome instability and cancer. We previously identified a spindle associated, mitotic phospho-protein, NUSAP1, as a substrate of ubiquitin mediated destruction (Emanuele et al, Cell 2011). Further, we showed that NUSAP1 interacts with a SUMO ligase during mitosis, implicated NUSAP1 in bridging the ubiquitin and SUMO systems (Mills et al, 2017). Determining how SUMO and ubiquitin coordinately control chromosome stability and how these systems are perturbed in disease is an area of ongoing study.
Global analysis of ubiquitin systems
The protein landscape is dynamically reorganized in response to environmental changes and stress, during development, throughout the cell cycle and in cancer . These dynamics are controlled, in part, by the targeted degradation of specific proteins. Two key challenges in the ubiquitin field are globally monitoring ubiquitin dynamics, and connecting enzymes and substrates, akin to matching transcription factors with their target genes. To address this challenge we are implementing technologies that assess global, proteome wide changes in protein stability using genetic and proteomic methods that we previously developed (Emanuele et al, Cell 2011).