PXD001501

PXD001501 is an original dataset announced via ProteomeXchange.

Title	Rb and the APC/C coactivator FZR1 determine CDK4/6-Cyclin D requirement in C. elegans and human cancer cells
Description	Cyclin dependent kinase 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry, at least in part through phosphorylation of the retinoblastoma tumor suppressor protein (Rb). The CDK4/6-cyclin D-Rb pathway is commonly deregulated in human cancer, often through CDK4/6 or D-type cyclin overexpression, or inactivation of the CDK4/6 antagonist p16/CDKN2A. Importantly, a substantial fraction of cancers depend on continuous CDK4/6-cyclin D kinase activity and are sensitive to CDK4/6-specific inhibitors. Here, we investigate critical CDK4/6-cyclin D functions that may determine the sensitivity to CDK4/6 inhibitors, making use of the essential roles of CDK4/6 (CDK-4) and cyclin D (CYD-1) in the nematode C. elegans. In an unbiased screen, we found that simultaneous loss of C. elegans Rb (lin-35) and down-regulation of the APC/C substrate specificity factor FZR1/Cdh1 completely overcomes CDK-4/CYD-1 requirement. Furthermore, CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 N-terminus that correspond to inactivating phosphorylations of the human homologs. Thus, CDK-4/CYD-1 appears to promote cell cycle entry by antagonizing not only transcriptional repression by LIN-35 Rb but also protein degradation by APC/CFZR-1. Simultaneous knockdown of Rb and FZR1 in human breast cancer cells synergistically overcomes arrest by the CDK4/6-specific inhibitor PD 00332991. These results reveal APC/CFZR1 as a putative CDK4/6-Cyclin D target and important contributing factor in the response to CDK4/6-inhibitor treatment.
HostingRepository	PRIDE
AnnounceDate	2016-07-05
AnnouncementXML	Submission_2016-07-05_05:50:55.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alba Cristobal
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Caenorhabditis elegans; NCBI TaxID: 6239;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue; phosphorylated residue
Instrument	LTQ Orbitrap Velos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2014-11-17 07:20:31	ID requested
⏵ 1	2016-07-05 05:50:56	announced

The I, Ruijtenberg S, Bouchet BP, Cristobal A, Prinsen MB, van Mourik T, Koreth J, Xu H, Heck AJ, Akhmanova A, Cuppen E, Boxem M, Mu, ñ, oz J, van den Heuvel S, Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells. Nat Commun, 6():5906(2015) [pubmed]

curator keyword: Biomedical

submitter keyword: Lin-35 Fzr1

Albert J.R. Heck
contact affiliation	Biomolecular Mass Spectrometry and Proteomics Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences Utrecht University Padualaan 8 3584 CH Utrecht The Netherlands
contact email	A.J.R.Heck@uu.nl
lab head
Alba Cristobal
contact affiliation	Utrecht University
contact email	a.cristobalgonzalezdedurana@uu.nl
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/2016/07/PXD001501

PRIDE project URI

• PRIDE
  1. PXD001501
     1. Label: PRIDE project
     2. Name: Rb and the APC/C coactivator FZR1 determine CDK4/6-Cyclin D requirement in C. elegans and human cancer cells