RGD Reference Report - Prolactin blocks nuclear translocation of VDR by regulating its interaction with BRCA1 in osteosarcoma cells. - Rat Genome Database

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Prolactin blocks nuclear translocation of VDR by regulating its interaction with BRCA1 in osteosarcoma cells.

Authors: Deng, C  Ueda, E  Chen, KE  Bula, C  Norman, AW  Luben, RA  Walker, AM 
Citation: Deng C, etal., Mol Endocrinol. 2009 Feb;23(2):226-36. doi: 10.1210/me.2008-0075. Epub 2008 Dec 12.
RGD ID: 10059411
Pubmed: PMID:19074549   (View Abstract at PubMed)
PMCID: PMC5419306   (View Article at PubMed Central)
DOI: DOI:10.1210/me.2008-0075   (Journal Full-text)

Based on their content of prolactin receptors, osteosarcoma cells were predicted to be responsive to prolactin (PRL), but whether PRL would be beneficial or contribute to pathogenesis was unclear. 1,25(OH)(2) vitamin D(3) [1alpha,25(OH)(2)D(3)] has antiproliferative effects on osteosarcoma cells, and a complex interregulatory situation exists between PRL and 1alpha,25(OH)(2)D(3). Using osteosarcoma cells, Western blot, real time RT-PCR, and promoter-luciferase assays, we have examined the interaction between PRL and 1alpha,25(OH)(2)D(3) and demonstrated that physiological concentrations of PRL block increased osteocalcin and vitamin D receptor (VDR) expression in response to 1alpha,25(OH)(2)D(3.) This blockade was shown to be the result of lack of nuclear accumulation of the VDR in response to 1alpha,25(OH)(2)D(3). Although inhibition of proteasomic degradation with MG132 had no effect on the VDR itself in a 30-min time frame, it relieved the blockade by PRL. Analysis of ubiquitinated proteins brought down by immunoprecipitation with anti-VDR showed PRL regulation of a 250-kDa protein-VDR complex. P250 was identified as the breast cancer tumor suppressor gene product, BRCA1, by Western blot of the VDR immunoprecipitate and confirmed by immunoprecipitation with anti-BRCA1 and blotting for the VDR in the absence and presence of PRL. Knockdown of BRCA1 inhibited nuclear translocation of the VDR and the ability of 1alpha,25(OH)(2)D(3) to induce the VDR. This, to our knowledge, is the first demonstration of a role for BRCA1 in nuclear accumulation of a steroid hormone and the first demonstration that PRL has the potential to affect the cell cycle through effects on BRCA1.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of protein import into nucleus  IMP 10059411 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding  IPIVdr (Rattus norvegicus)10059411 RGD 
protein binding  IPIBrca1 (Rattus norvegicus)10059411 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Brca1  (BRCA1, DNA repair associated)
Vdr  (vitamin D receptor)


Additional Information