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SUMMARY:Breaking the cycle: mechanisms that underpin proliferation-dormanc
 y switches - Tony Ly - University of Dundee
DTSTART:20251030T150000Z
DTEND:20251030T160000Z
UID:TALK235564@talks.cam.ac.uk
CONTACT:90994
DESCRIPTION:I will present our work investigating the mechanisms that unde
 rpin proliferation-dormancy state changes. Most cells in our body are not 
 actively undergoing cell division cycles and are dormant. The ability for 
 cells to exit dormancy and re-enter the cell cycle is crucial for tissue r
 enewal and immune responses. These mechanisms are highly regulated and are
  frequently altered in cancer to fuel uncontrolled proliferation. Cellular
  senescence is another dormant state\, but unlike quiescence\, these cells
  are prevented from re-entering the cell cycle and thereby potentially con
 tribute to neoplastic disease. It is crucial that we understand the mechan
 isms that control proliferation-dormancy state switches. \nTo elucidate th
 ese mechanisms\, we have studied the exemplar case of Cdk4/6 inhibitors an
 d cultured human epithelial cells. Short term CDK4/6 inhibitor treatment r
 esults in quiescence and reversible cell cycle re-entry. Prolonged CDK4/6 
 inhibitor treatment results in cellular senescence. I will show that prolo
 nged treatment results in excessive increases in cell size\, a phenotype w
 e call cell overgrowth. Cell overgrowth promotes senescence via biphasic p
 21 induction. During proliferative arrest\, overgrowth is accompanied by i
 mbalanced proteome scaling and osmotic stress\, resulting in increased p21
  in a p38- and p53-dependent manner. Aberrantly large cells that prolifera
 te following release from CDK4/6i experience a second phase of p21 inducti
 on from replication stress and p21/p53-dependent cell cycle exit. The dorm
 ancy fate choice is determined by accumulated p21\, integrating past stres
 ses experienced during CDK4/6i arrest and release. These mechanisms help e
 xplain why aberrantly large cells are sensitized to senescence induction\,
  and by extension\, why cell hypertrophy is a feature frequently associate
 d with senescence. \nWhy does excessive cell size promote senescence? We h
 ypothesize that allometric scaling of the proteome with excessive cell siz
 e challenges cellular homeostasis to trigger senescence. I will present un
 published work to characterize remodeling of the cellular proteome in huma
 n fibroblast and epithelial cells in response to various senescence induce
 rs\, including oncogenes\, acute DNA damage\, and chemotherapies\, compari
 ng these to quiescent and asynchronous controls. In addition to protein ab
 undance\, we have measured protein turnover\, subcellular localization and
  secreted proteins to develop a multidimensional map of stress-induced sen
 escence.\n
LOCATION:Jean Thomas Lecture theatre\, Sanger Building\, Tennis Court Road
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