scholarly journals Activity of Retinoic Acid Receptor-alpha Is Directly Regulated at Its Protein Kinase A Sites in Response to Follicle-Stimulating Hormone Signaling

Endocrinology ◽  
2010 ◽  
Vol 151 (5) ◽  
pp. 2361-2372 ◽  
Author(s):  
Nadine C. Santos ◽  
Kwan Hee Kim

Retinoic acid receptor-α (RARA) is crucial for germ cell development in the testis, as shown by the degenerated testis in Rara gene knockout mice, which are sterile. Similarly, FSH is known to regulate Sertoli cell proliferation and differentiation, indirectly controlling the quantity of the spermatogenic output. Interestingly, FSH inhibited, via activation of FSH receptor, cAMP, and protein kinase A (PKA), the nuclear localization and transcriptional activity of RARA. Given that retinoic acid, the ligand for RARA, is known to regulate cell proliferation and differentiation, we investigated whether FSH regulates RARA by a direct posttranslational phosphorylation mechanism. Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity. The negative charges at the PKA sites, whether they are from glutamic acids or phosphorylation of serines, decreased the nuclear localization of RARA, heterodimerization with retinoid X receptor-α, and the transcriptional activity of the receptor. On the other hand, the double-alanine mutant that cannot be phosphorylated at the 219 and 369 amino acid positions did not respond to cAMP and PKA activation. Wild-type and double-mutant RARA interacted with PKA, but only in the presence of cAMP or FSH. These results together suggest that FSH may regulate cell proliferation and differentiation of Sertoli cells, at least partially, by directly affecting the PKA sites of RARA and controlling the transcriptional function of the receptor.

1995 ◽  
Vol 9 (7) ◽  
pp. 860-871 ◽  
Author(s):  
C Rochette-Egly ◽  
M Oulad-Abdelghani ◽  
A Staub ◽  
V Pfister ◽  
I Scheuer ◽  
...  

2014 ◽  
Vol 28 (5) ◽  
pp. 681-695 ◽  
Author(s):  
Ana Sastre-Perona ◽  
Pilar Santisteban

Abstract The Wnt/β-catenin pathway has been associated with thyroid cell growth and tumorigenesis. However, little is known regarding its involvement in the response to the key regulators of thyroid cell proliferation and differentiation. Here we show that TSH and IGF-1 increase β-catenin nuclear accumulation and its transcriptional activity in differentiated thyroid cells. This effect takes place in a Wnt-independent manner because TSH and IGF-1, through the activation of protein kinase A and protein kinase B/Akt, phosphorylate β-catenin at S552 and S675, which results in β-catenin release from E-cadherin at the adherens junctions. Nuclear β-catenin regulates thyroid cell proliferation, because its silencing or the overexpression of a dominant-negative form of T-cell factor 4 resulted in reduced levels of cyclin D1 and DNA synthesis. Furthermore, the β-catenin silencing markedly reduced the expression of Pax8, the main transcription factor involved in epithelial thyroid cell differentiation. Finally, we observed that β-catenin physically interacts with the transcription factor Pax8, increasing its transcriptional activity on the sodium iodide symporter (NIS) gene, a critical gene required for thyroid cell physiology. Taken together, our findings show that β-catenin plays a not yet described role in thyroid function including a functional interaction with Pax8.


PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e109523 ◽  
Author(s):  
Mei Zhang ◽  
Emilia Mahoney ◽  
Tao Zuo ◽  
Parmeet K. Manchanda ◽  
Ramana V. Davuluri ◽  
...  

2003 ◽  
Vol 278 (25) ◽  
pp. 22586-22595 ◽  
Author(s):  
Alpana Ray ◽  
Papiya Ray ◽  
Nicole Guthrie ◽  
Arvind Shakya ◽  
Deepak Kumar ◽  
...  

2008 ◽  
Vol 93 (3) ◽  
pp. 1020-1029 ◽  
Author(s):  
Audrey J. Robinson-White ◽  
Hui-Pin Hsiao ◽  
Wolfgang W. Leitner ◽  
Elizabeth Greene ◽  
Andrew Bauer ◽  
...  

Abstract Purpose: Protein kinase A (PKA) affects cell proliferation in many cell types and is a potential target for cancer treatment. PKA activity is stimulated by cAMP and cAMP analogs. One such substance, 8-Cl-cAMP, and its metabolite 8-Cl-adenosine (8-Cl-ADO) are known inhibitors of cancer cell proliferation; however, their mechanism of action is controversial. We have investigated the antiproliferative effects of 8-Cl-cAMP and 8-CL-ADO on human thyroid cancer cells and determined PKA’s involvement. Experimental Design: We employed proliferation and apoptosis assays and PKA activity and cell cycle analysis to understand the effect of 8-Cl-ADO and 8-Cl-cAMP on human thyroid cancer and HeLa cell lines. Results: 8-Cl-ADO inhibited proliferation of all cells, an effect that lasted for at least 4 d. Proliferation was also inhibited by 8-Cl-cAMP, but this inhibition was reduced by 3-isobutyl-1-methylxanthine; both drugs stimulated apoptosis, and 3-isobutyl-1-methylxanthine drastically reduced 8-Cl-cAMP-induced cell death. 8-Cl-ADO induced cell accumulation in G1/S or G2/M cell cycle phases and differentially altered PKA activity and subunit levels. PKA stimulation or inhibition and adenosine receptor agonists or antagonists did not significantly affect proliferation. Conclusions: 8-Cl-ADO and 8-Cl-cAMP inhibit proliferation, induce cell cycle phase accumulation, and stimulate apoptosis in thyroid cancer cells. The effect of 8-Cl-cAMP is likely due to its metabolite 8-Cl-ADO, and PKA does not appear to have direct involvement in the inhibition of proliferation by 8-Cl-ADO. 8-Cl-ADO may be a useful therapeutic agent to be explored in aggressive thyroid cancer.


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