A-kinase anchoring protein 13 interacts with the vitamin D receptor to alter vitamin D-dependent gene activation in uterine leiomyoma cells.

Abstract

OBJECTIVE:

To determine if A-kinase anchoring protein 13 (AKAP13) interacts with the vitamin D receptor (VDR) to alter vitamin D-dependent signaling in fibroid cells. Uterine leiomyomas (fibroids) are characterized by a fibrotic extracellular matrix and are associated with vitamin D deficiency. Treatment with vitamin D (1,25-dihydroxyvitamin D3) reduces fibroid growth and extracellular matrix gene expression. A-kinase anchoring protein 13 is overexpressed in fibroids and interacts with nuclear hormone receptors, but it is not known whether AKAP13 may interact with the VDR to affect vitamin D signaling in fibroids.

DESIGN:

Laboratory studies.

SETTING:

Translational science laboratory.

INTERVENTION(S):

Human immortalized fibroid or myometrial cells were treated with 1,25-hydroxyvitamin D3 (1,25(OH)2D3) and transfected using expression constructs for AKAP13 or AKAP13 mutants, RhoQL, C3 transferase, or small interfering ribonucleic acids (RNAs).

MAIN OUTCOME MEASURE(S):

Messenger ribonucleic acid (mRNA) levels of AKAP13, fibromodulin, and versican as measured by quantitative real-time polymerase chain reaction. Glutathione S-transferase-binding assays. Vitamin D-dependent gene activation as measured by luciferase assays.

RESULT(S):

1,25(OH)2D3 resulted in a significant reduction in mRNA levels encoding AKAP13, versican, and fibromodulin. Small interfering RNA silencing of AKAP13 decreased both fibromodulin and versican mRNA levels. Glutathione S-transferase-binding assays revealed that AKAP13 bound to the VDR through its nuclear receptor interacting region. Cotransfection of AKAP13 and VDR significantly reduced vitamin D-dependent gene activation. RhoA pathway inhibition partially relieved repression of vitamin D-dependent gene activation by AKAP13.

CONCLUSION(S):

These data suggest that AKAP13 inhibited the vitamin D receptor activation by a mechanism that required, at least in part, RhoA activation.

• Authors: Chantel I Cross, Paul H Driggers, Breanne E McCarthy, Maya Diab, Joshua Brennan, James H Segars
• Journal: F&S science (F S Sci) Vol. 2 Issue 3 Pg. 303-314 (08 2021) ISSN: 2666-335X [Electronic] United States
• PMID: 35560280 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Chemical References

• A Kinase Anchor Proteins
• RNA, Messenger
• Receptors, Calcitriol
• Vitamins
• Fibromodulin
• Versicans
• Vitamin D
• Glutathione Transferase

Topics

• A Kinase Anchor Proteins (genetics)
• Female
• Fibromodulin (genetics)
• Glutathione Transferase (genetics)
• Humans
• Leiomyoma (genetics)
• RNA, Messenger (metabolism)
• Receptors, Calcitriol (genetics)
• Transcriptional Activation
• Versicans (genetics)
• Vitamin D (pharmacology)
• Vitamins