PXD036519

PXD036519 is an original dataset announced via ProteomeXchange.

Title	CDK4/6 inhibitor-mediated cell overgrowth triggers an osmotic stress response
Description	Cell size and the cell cycle are intrinsically coupled and abnormal increases in cell size are associated with senescence and permanent cell cycle arrest. The mechanism by which overgrowth primes cells to withdraw from the cell cycle remains unknown. We investigate this here using CDK4/6 inhibitors that arrest cell cycle progression during G0/G1 and are used in the clinic to treat ER+/HER2- metastatic breast cancer. We demonstrate that CDK4/6 inhibition promotes cellular overgrowth during G0/G1, causing p38MAPK-p53-p21-dependent cell cycle withdrawal. We find that cell cycle withdrawal is triggered by two waves of p21 induction. First, overgrowth during a long-term G0/G1 arrest induces an osmotic stress response. This stress response produces the first wave of p21 induction. Second, when CDK4/6 inhibitors are removed, a fraction of cells escape long term G0/G1 arrest and enter S-phase where overgrowth-driven replication stress results in a second wave of p21 induction that causes cell cycle withdrawal from G2, or the subsequent G1. We propose a model whereby both waves of p21 induction contribute to promote permanent cell cycle arrest. This model could explain why cellular hypertrophy is associated with senescence and why CDK4/6 inhibitors have long-lasting effects in patients.
HostingRepository	PRIDE
AnnounceDate	2023-11-27
AnnouncementXML	Submission_2023-11-27_02:44:29.790.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tony Ly
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-05 09:13:44	ID requested
⏵ 1	2023-11-27 02:44:30	announced

10.1016/j.molcel.2023.10.016;

Crozier L, Foy R, Adib R, Kar A, Holt JA, Pareri AU, Valverde JM, Rivera R, Weston WA, Wilson R, Regnault C, Whitfield P, Badonyi M, Bennett LG, Vernon EG, Gamble A, Marsh JA, Staples CJ, Saurin AT, Barr AR, Ly T, CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Mol Cell, 83(22):4062-4077.e5(2023) [pubmed]

submitter keyword: LC-MS/MS, DIA, cell growth, cell cycle

Tony Ly
contact affiliation	Centre for Gene Regulation and Expression University of Dundee
contact email	tly@dundee.ac.uk
lab head
Tony Ly
contact affiliation	University of Dundee
contact email	tly@dundee.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/11/PXD036519

PRIDE project URI

• PRIDE
  1. PXD036519
     1. Label: PRIDE project
     2. Name: CDK4/6 inhibitor-mediated cell overgrowth triggers an osmotic stress response