Linked Life Data

18794799

Source:http://linkedlifedata.com/resource/pubmed/id/18794799

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
57
pubmed:dateCreated
2008-12-4
pubmed:abstractText
Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We designed two Protacs that contain the peptide 'degron' from hypoxia-inducible factor-1alpha, which binds to the Von-Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-alpha (ERalpha; Protac-B). We hypothesized that these Protacs would recruit hormone receptors to the VHL E3 ligase complex, resulting in the degradation of receptors, and decreased proliferation of hormone-dependent cell lines. Treatment of estrogen-dependent breast cancer cells with Protac-B induced the degradation of ERalpha in a proteasome-dependent manner. Protac-B inhibited the proliferation of ERalpha-dependent breast cancer cells by inducing G(1) arrest, inhibition of retinoblastoma phosphorylation and decreasing expression of cyclin D1, progesterone receptors A and B. Protac-B treatment did not affect the proliferation of estrogen-independent breast cancer cells that lacked ERalpha expression. Similarly, Protac-A treatment of androgen-dependent prostate cancer cells induced G(1) arrest but did not affect cells that do not express AR. Our results suggest that Protacs specifically inhibit the proliferation of hormone-dependent breast and prostate cancer cells through degradation of the ERalpha and AR, respectively.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1476-5594
pubmed:author
pubmed:issnType
Electronic
pubmed:day
4
pubmed:volume
27
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7201-11
pubmed:meshHeading
pubmed-meshheading:18794799-Antineoplastic Agents, pubmed-meshheading:18794799-Blotting, Western, pubmed-meshheading:18794799-Breast Neoplasms, pubmed-meshheading:18794799-Cell Cycle, pubmed-meshheading:18794799-Cell Line, Tumor, pubmed-meshheading:18794799-Cell Proliferation, pubmed-meshheading:18794799-Dihydrotestosterone, pubmed-meshheading:18794799-Drug Delivery Systems, pubmed-meshheading:18794799-Estradiol, pubmed-meshheading:18794799-Estrogen Receptor alpha, pubmed-meshheading:18794799-Female, pubmed-meshheading:18794799-Flow Cytometry, pubmed-meshheading:18794799-Humans, pubmed-meshheading:18794799-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:18794799-Male, pubmed-meshheading:18794799-Neoplasms, Hormone-Dependent, pubmed-meshheading:18794799-Prostatic Neoplasms, pubmed-meshheading:18794799-Proteasome Endopeptidase Complex, pubmed-meshheading:18794799-Receptors, Androgen, pubmed-meshheading:18794799-Receptors, Steroid, pubmed-meshheading:18794799-Recombinant Fusion Proteins, pubmed-meshheading:18794799-Ubiquitination
pubmed:year
2008
pubmed:articleTitle
Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer.
pubmed:affiliation
Department of Pediatrics, Gwynne Hazen Cherry Laboratories, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1752, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural