PXD001154

PXD001154 is an original dataset announced via ProteomeXchange.

Title	SIRT6 phosphorylation
Description	Sirtuin 6 (SIRT6) is associated with longevity and was recently established as a tumor suppressor. Hence, identifying the molecular regulators of SIRT6 might enable its activation therapeutically in cancer patients. We found that SIRT6 was phosphorylated by the kinase AKT1 at Ser338, which induces its interaction with and ubiquitination by MDM2, priming it for protease-dependent degradation. The survival of patients with breast cancers positively correlated with the abundance of SIRT6 and inversely correlated with the phosphorylation of SIRT6 at Ser338. In a large panel of breast tumor biopsies, SIRT6 abundance inversely correlated with the abundance of phosphorylated AKT. Inhibiting AKT or preventing SIRT6 phosphorylation by mutating Ser338 prevented the degradation of SIRT6 mediated by MDM2, suppressed the proliferation of breast cancer cells in culture, and inhibited the growth of breast tumor xenografts in mice. Overexpressing MDM2 decreased the abundance of SIRT6 in cells, whereas overexpressing an E3 ligase-deficient MDM2 or knocking down endogenous MDM2 increased SIRT6 abundance. Knocking down SIRT6 decreased the sensitivity of a breast cancer cell line to trastuzumab, whereas overexpression of a non-phosphorylatable SIRT6 mutant increased trastuzumab sensitivity in a resistant subculture. Thus, stabilizing SIRT6 may be a clinical strategy for overcoming trastuzumab resistance in breast cancer patients.
HostingRepository	PRIDE
AnnounceDate	2016-07-08
AnnouncementXML	Submission_2016-07-08_08:06:28.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Umadevi Thirumurthi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q TRAP

Revision	Datetime	Status	ChangeLog Entry
0	2014-07-17 00:34:04	ID requested
1	2016-07-06 14:15:08	announced
⏵ 2	2016-07-08 08:06:29	announced	Updated project metadata.

Thirumurthi U, Shen J, Xia W, LaBaff AM, Wei Y, Li CW, Chang WC, Chen CH, Lin HK, Yu D, Hung MC, MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer. Sci Signal, 7(336):ra71(2014) [pubmed]

ProteomeXchange project tag: Biology/Disease-Driven Human Proteome Project (B/D-HPP), Human Proteome Project

curator keyword: Biomedical

submitter keyword: SIRT6, phosphorylation

Mien-Chie Hung
contact affiliation	UT MD Anderson Cancer Center
contact email	mhung@mdanderson.org
lab head
Umadevi Thirumurthi
contact affiliation	UT MD Anderson Cancer Center
contact email	Umadevi.Thirumurthi@uth.tmc.edu
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/PXD001154

PRIDE project URI

• PRIDE
  1. PXD001154
     1. Label: PRIDE project
     2. Name: SIRT6 phosphorylation