TY - JOUR
T1 - 1,25-Dihydroxyvitamin D 3 regulates PTHrP expression via transcriptional, post-transcriptional and post-translational pathways
AU - Bhatia, Vandanajay
AU - Mula, Ramanjaneya V.
AU - Falzon, Miriam
N1 - Funding Information:
We thank Dr. Milan Uskokovic, Hoffman La Roche, for supplying 1,25-dihydroxyvitamin D 3 , Dr. Zhor Bouizar, INSERM, for supplying the PTHrP promoter constructs, and Dr. David Konkel for critically editing the manuscript. This work was supported by NIH grant CA83940 .
PY - 2011/8/6
Y1 - 2011/8/6
N2 - Parathyroid hormone-related protein (PTHrP) increases the growth and osteolytic potential of prostate cancer cells, making it important to control PTHrP expression. PTHrP expression is suppressed by 1,25-dihydroxyvitamin D 3 (1,25D). The aim of this study was to identify the pathways via which 1,25D exerts these effects. Our main findings are that 1,25D regulates PTHrP levels via multiple pathways in PC-3 and C4-2 (human prostate cancer) cell lines, and regulation is dependent on VDR expression. The human PTHrP gene has three promoters (P); PC-3 cells preferentially utilize P2 and P3, while C4-2 cells preferentially utilize P1. 1,25D regulates PTHrP transcriptional activity from both P1 and P3. The 1,25D-mediated decrease in PTHrP mRNA levels also involves a post-transcriptional pathway since 1,25D decreases PTHrP mRNA stability. 1,25D also suppresses PTHrP expression directly at the protein level by increasing its degradation. Regulation of PTHrP levels is dependent on VDR expression, as using siRNAs to deplete VDR expression negates the 1,25D-mediated downregulation of PTHrP expression. These results indicate the importance of maintaining adequate 1,25D levels and VDR status to control PTHrP levels.
AB - Parathyroid hormone-related protein (PTHrP) increases the growth and osteolytic potential of prostate cancer cells, making it important to control PTHrP expression. PTHrP expression is suppressed by 1,25-dihydroxyvitamin D 3 (1,25D). The aim of this study was to identify the pathways via which 1,25D exerts these effects. Our main findings are that 1,25D regulates PTHrP levels via multiple pathways in PC-3 and C4-2 (human prostate cancer) cell lines, and regulation is dependent on VDR expression. The human PTHrP gene has three promoters (P); PC-3 cells preferentially utilize P2 and P3, while C4-2 cells preferentially utilize P1. 1,25D regulates PTHrP transcriptional activity from both P1 and P3. The 1,25D-mediated decrease in PTHrP mRNA levels also involves a post-transcriptional pathway since 1,25D decreases PTHrP mRNA stability. 1,25D also suppresses PTHrP expression directly at the protein level by increasing its degradation. Regulation of PTHrP levels is dependent on VDR expression, as using siRNAs to deplete VDR expression negates the 1,25D-mediated downregulation of PTHrP expression. These results indicate the importance of maintaining adequate 1,25D levels and VDR status to control PTHrP levels.
KW - 1,25-Dihydroxyvitamin D
KW - Negative vitamin D response element
KW - Parathyroid hormone-related protein
KW - Prostate cancer
KW - Vitamin D receptor
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U2 - 10.1016/j.mce.2011.05.025
DO - 10.1016/j.mce.2011.05.025
M3 - Article
C2 - 21664243
AN - SCOPUS:79960847097
SN - 0303-7207
VL - 342
SP - 32
EP - 40
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
IS - 1-2
ER -