A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells

Sinnie Sin Man Ng, Soledad Jorge, Minnie Malik, Joy Britten, Szu Chi Su, Charles R. Armstrong, Joshua T. Brennan, Sydney Chang, Kimberlyn Maravet Baig, Paul H. Driggers, James Segars

Research output: Contribution to journalArticle

Abstract

Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.

Original languageEnglish (US)
Pages (from-to)970-980
Number of pages11
JournalThe Journal of clinical endocrinology and metabolism
Volume104
Issue number3
DOIs
StatePublished - Mar 1 2019

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Leiomyoma
Protein Kinases
Progesterone
Progesterone Receptors
Phosphotransferases
Proteins
Chemical activation
p38 Mitogen-Activated Protein Kinases
Cytoplasmic and Nuclear Receptors
Luciferases
Modulators
Mechanical Stress
Glutathione
Tumors
Assays
COS Cells
Genes
Cells
Tissue
Ligands

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells. / Ng, Sinnie Sin Man; Jorge, Soledad; Malik, Minnie; Britten, Joy; Su, Szu Chi; Armstrong, Charles R.; Brennan, Joshua T.; Chang, Sydney; Baig, Kimberlyn Maravet; Driggers, Paul H.; Segars, James.

In: The Journal of clinical endocrinology and metabolism, Vol. 104, No. 3, 01.03.2019, p. 970-980.

Research output: Contribution to journalArticle

Ng, SSM, Jorge, S, Malik, M, Britten, J, Su, SC, Armstrong, CR, Brennan, JT, Chang, S, Baig, KM, Driggers, PH & Segars, J 2019, 'A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells', The Journal of clinical endocrinology and metabolism, vol. 104, no. 3, pp. 970-980. https://doi.org/10.1210/jc.2018-01216
Ng, Sinnie Sin Man ; Jorge, Soledad ; Malik, Minnie ; Britten, Joy ; Su, Szu Chi ; Armstrong, Charles R. ; Brennan, Joshua T. ; Chang, Sydney ; Baig, Kimberlyn Maravet ; Driggers, Paul H. ; Segars, James. / A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells. In: The Journal of clinical endocrinology and metabolism. 2019 ; Vol. 104, No. 3. pp. 970-980.
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AU - Jorge, Soledad

AU - Malik, Minnie

AU - Britten, Joy

AU - Su, Szu Chi

AU - Armstrong, Charles R.

AU - Brennan, Joshua T.

AU - Chang, Sydney

AU - Baig, Kimberlyn Maravet

AU - Driggers, Paul H.

AU - Segars, James

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N2 - Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.

AB - Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.

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