original artwork by Allie Mills

original artwork by Allie Mills


Ubiquitin signaling in cell cycle control

The ubiquitin proteasome system plays a vital role in homeostatic cell cycle progression and its dysfunction is implicated in cancer proliferation. Our goal is to investigate mechanisms that promote cell cycle progression, examine how they are aberrantly regulated in malignancies, and to determine how they support cancer growth.

 

 

The cancer cell cycle: The G1/S boundary represents a major barrier to oncogenic transformation. 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, mitogen responsive kinase AKT (Choudhury et al, 2017). We are investigating additional targets controlled by these two E3 enzymes, and the mechanisms by which they promote normal and cancer cell cycles.

 

Cell cycle transcription: Ubiquitin signaling plays a vital role in shaping transcriptional output. In fact, ubiquitin was identified by virtue of its conjugation to histones, prior to the realization of its role in protein destruction. We are specifically interested in a late cell cycle transcription factor FoxM1, that is hyper-activated in several malignancies, including serous ovarian cancer and triple-negative breast cancer. We recently discovered a component in the ubiquitin system that, paradoxically, promotes FoxM1 degradation and activation (Wang et al, 2016). We are focused on mechanisms by which FoxM1 and how it could be attacked for therapeutic benefit.

 

Chromosome segregation: Chromosome segregation fidelity during cell division is essential to prevent chromosome instability and caner. We previously identified a spindle associated, mitotic phospho-protein, Nusap1, as a substrate of ubiquitin mediated degradation (Emanuele et al, Cell 2011). In a more recent study, 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 mitotic progression and how these systems could perturbed in disease is an area of ongoing study.

 

Global analysis of the ubiquitin modified proteome: Human cells encode more than twenty thousand unique proteins.  The protein landscape is dynamically reorganized in response to environmental changes and stress, during development, throughout the cell cycle and during cancer initiation and progression. These dynamics are controlled, in part, by targeted degradation of specific proteins. A key challenge in the ubiquitin field is global monitoring of ubiquitin dynamics and connecting ligases 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).