CBP/p300 induction is required for retinoic acid sensitivity in human mammary cells.
The coactivators CBP and p300 are recruited by retinoic acid receptors (RARs) during retinoid mediated transcriptional regulation. To assess the role of CBP/p300 in all-trans-retinoic acid (ATRA)-mediated growth arrest in mammary epithelial cells, two systems were tested: (1) ATRA resistant MCF-7 cells were transduced with a functional RAR-beta 2; (2) normal human mammary epithelial cells (HMECs) were transduced with a pan-RAR dominant negative, RAR-alpha 403. Expression of RAR-beta 2 in MCF-7 cells resulted in increased sensitivity to ATRA-induced growth arrest and correlated with induction of CBP/p300 mRNA and protein. Inhibition of RAR function in HMECs resulted in resistance to ATRA-induced growth arrest and loss of CBP/p300 induction. Antisense suppression of CBP/p300 in HMECs resulted in decreased retinoic acid response element reporter trans-activation and decreased ATRA-mediated growth arrest. Thus, in human mammary epithelial cells, CBP/p300 were both modulated by an ATRA signaling pathway and were required for a normal response to ATRA.
Dietze
Eric C
EC
Division of Medical Oncology and Transplantation, Duke University Medical Center, Box 2628, Durham, NC 27710, USA.
Troch
Michelle M
MM
Bowie
Michelle L
ML
Yee
Lisa
L
Bean
Gregory R
GR
Seewaldt
Victoria L
VL
D001940:Breast / Q000166:cytology / Q000378:metabolism*; D050882:CREB-Binding Protein; D002453:Cell Cycle / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators; C082925:retinoic acid receptor beta; D014212:Tretinoin; D050882:CREB-Binding Protein; C494363:CREBBP protein, human