title: Crosstalk between the peroxisome proliferator-activated receptor γ (PPARγ) and the vitamin D receptor (VDR) in human breast cancer cells: PPARγ binds to VDR and inhibits 1α,25-dihydroxyvitamin D3 mediated transactivation.
abstract: Heterodimerization and cross-talk between nuclear hormone receptors often occurs. For example, estrogen receptor alpha (ERα) physically binds to peroxisome proliferator-activated receptor gamma (PPARγ) and inhibits its transcriptional activity. The interaction between PPARγ and the vitamin D receptor (VDR) however, is unknown. Here, we elucidate the molecular mechanisms linking PPARγ and VDR signaling, and for the first time we show that PPARγ physically associates with VDR in human breast cancer cells. We found that overexpression of PPARγ decreased 1α,25-dihydroxyvitamin D(3) (1,25D(3)) mediated transcriptional activity of the vitamin D target gene, CYP24A1, by 49% and the activity of VDRE-luc, a vitamin D responsive reporter, by 75% in T47D human breast cancer cells. Deletion mutation experiments illustrated that helices 1 and 4 of PPARγ's hinge and ligand binding domains, respectively, governed this suppressive function. Additionally, abrogation of PPARγ's AF2 domain attenuated its repressive action on 1,25D(3) transactivation, indicating that this domain is integral in inhibiting VDR signaling. PPARγ was also found to compete with VDR for their binding partner retinoid X receptor alpha (RXRα). Overexpression of RXRα blocked PPARγ's suppressive effect on 1,25D(3) action, enhancing VDR signaling. In conclusion, these observations uncover molecular mechanisms connecting the PPARγ and VDR pathways.
authors.affiliation: Cancer Biology Division, IIT Research Institute, 10 West 35th Street, Chicago, IL 60616, USA.
authors.forename: Fatouma
authors.initials: F
authors.lastname: Alimirah
authors.forename: Xinjian
authors.initials: X
authors.lastname: Peng
authors.forename: Liang
authors.initials: L
authors.lastname: Yuan
authors.forename: Rajeshwari R
authors.initials: RR
authors.lastname: Mehta
authors.forename: Andreas
authors.initials: A
authors.lastname: von Knethen
authors.forename: Divaker
authors.initials: D
authors.lastname: Choubey
authors.forename: Rajendra G
authors.initials: RG
authors.lastname: Mehta
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020239:Receptor Cross-Talk / Q000502:physiology*; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D047495:PPAR gamma; D018167:Receptors, Calcitriol; D047490:Retinoid X Receptor alpha; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase