PXD009133

PXD009133 is an original dataset announced via ProteomeXchange.

Title	Screening in Human Cardiac Organoids Identifies a Critical Role for the Mevalonate Pathway in Cardiomyocyte Proliferation
Description	Re-induction of endogenous proliferation is a promising regeneration strategy for post-mitotic organs. For heart regeneration, we recently discovered that dual inhibition of both GSK3 and MST1 is required for proliferation in mature human cardiac organoids1. However, the mechanisms of action are not yet understood. Here, we de-convolute the mitogenic response using proteomics and report that GSK3 inhibition activates a cell cycle network whereas MST1 inhibition drives the mevalonate pathway. Screening of an additional 105 compounds identified a p38 inhibitor, which activated a cell cycle network, as well as an inhibitor of TGFBR, which activated the mevalonate pathway; combinatorial treatment with these two inhibitors also resulted in synergistic cell cycle activation. The mevalonate pathway which was consistently activated under the most robust proliferative conditions, is down-regulated during in vivo maturation when cardiomyocyte regenerative capacity ceases and inhibition of the mevalonate pathway abolished the myocyte proliferative response to mitogens. Taken together, our findings suggest that the mevalonate pathway synergises with mitogenic agents to enable mature cardiomyocytes to re-enter the cell cycle. These findings have important ramifications for development of cardiac regenerative therapeutics.
HostingRepository	PRIDE
AnnounceDate	2019-03-13
AnnouncementXML	Submission_2019-03-12_17:35:46.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Benjamin Parker
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2018-03-08 01:04:59	ID requested
⏵ 1	2019-03-12 17:35:47	announced

Dataset with its publication pending

curator keyword: Biological, Biomedical

submitter keyword: cardiac organoids

Benjamin Parker
contact affiliation	The University of Sydney
contact email	benjamin.parker@sydney.edu.au
lab head
Benjamin Parker
contact affiliation	The University of Sydney
contact email	benjamin.parker@sydney.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD009133
     1. Label: PRIDE project
     2. Name: Screening in Human Cardiac Organoids Identifies a Critical Role for the Mevalonate Pathway in Cardiomyocyte Proliferation