scholarly journals Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation

2013 ◽  
Vol 27 (11) ◽  
pp. 1223-1232 ◽  
Author(s):  
F.-X. Yu ◽  
Y. Zhang ◽  
H. W. Park ◽  
J. L. Jewell ◽  
Q. Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Hippo Pathway ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
The Hippo Pathway ◽  
Kinase A

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
Keyword(s):  
Cell Proliferation ◽  
Retinoic Acid ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Nuclear Localization ◽  
Transcriptional Activity ◽  
Retinoic Acid Receptor ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Kinase A

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.

scholarly journals Protein Kinase A-Independent Inhibition of Proliferation and Induction of Apoptosis in Human Thyroid Cancer Cells by 8-Cl-Adenosine

2008 ◽  
Vol 93 (3) ◽  
pp. 1020-1029 ◽  
Author(s):  
Audrey J. Robinson-White ◽  
Hui-Pin Hsiao ◽  
Wolfgang W. Leitner ◽  
Elizabeth Greene ◽  
Andrew Bauer ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cancer Cells ◽  
Human Thyroid ◽  
Inhibition Of Proliferation ◽  
Thyroid Cancer Cells ◽  
Kinase A

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.

scholarly journals Membrane-Bound Protein Kinase A Inhibits Smooth Muscle Cell Proliferation In Vitro and In Vivo by Amplifying cAMP–Protein Kinase A Signals

2001 ◽  
Vol 88 (3) ◽  
pp. 319-324 ◽  
Author(s):  
Ciro Indolfi ◽  
Eugenio Stabile ◽  
Carmela Coppola ◽  
Adriana Gallo ◽  
Cinzia Perrino ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Protein Kinase ◽  
Smooth Muscle Cell ◽  
Protein Kinase A ◽  
Membrane Bound ◽  
Proliferation In Vitro ◽  
Kinase A

scholarly journals Expression of p27Kip1 in Osteoblast-Like Cells during Differentiation with Parathyroid Hormone*

Endocrinology ◽  
1997 ◽  
Vol 138 (5) ◽  
pp. 1995-2004 ◽  
Author(s):  
Takehisa Onishi ◽  
Keith Hruska
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Osteogenic Sarcoma ◽  
S Phase ◽  
G1 Phase ◽  
Osteoblastic Cell ◽  
Cyclin Dependent Kinases ◽  
Kinase A

Abstract PTH is a major systemic regulator of bone metabolism and plays an important role in both bone formation and resorption. PTH either inhibits or stimulates osteoblastic cell proliferation depending on the model that is studied. We analyzed the cell cycle of the UMR-106 cell line, a relatively differentiated osteoblastic osteogenic sarcoma line in which PTH is known to inhibit proliferation but the mechanism of action is unknown. PTH decreased the proportion of cells in S phase and increased the number of G1 phase cells. We examined the effect of PTH on the regulators of the G1 phase cyclin-dependent kinases and found that PTH increased p27Kip1, but not p21Cip1, levels. This effect was mimicked by 8-bromo-cAMP, but not by phorbol 12-myristate 13-acetate. The protein kinase A inhibitor KT5720 abolished the effect of PTH on the increase in p27Kip1 expression. PTH increased CDK2-associated p27Kip1 without affecting the levels of CDK2. CDK2 activity was down-regulated by both PTH and 8-bromo-cAMP treatment. These data suggest that PTH blocks entry of cells into S phase and inhibits cell proliferation as the consequence of an increase in p27Kip1, which is mediated through the protein kinase A pathway. The inhibition of G1 cyclin-dependent kinases by p27Kip1 could cause a reduction of phosphorylation of key substrates and inactivation of transcription factors essential for entry into S phase. The inhibition of cell cycle progression through PKA-mediated p27Kip1 induction might play an important role in PTH-induced differentiation of osteoblasts.

scholarly journals 8-Cl-Adenosine Inhibits Proliferation and Causes Apoptosis in B-Lymphocytes via Protein Kinase A-Dependent and Independent Effects: Implications for Treatment of Carney Complex-Associated Tumors

2009 ◽  
Vol 94 (10) ◽  
pp. 4061-4069 ◽  
Author(s):  
Audrey J. Robinson-White ◽  
Ioannis Bossis ◽  
Hui-Pin Hsiao ◽  
Maria Nesterova ◽  
Wolfgang W. Leitner ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
B Lymphocytes ◽  
Therapeutic Agent ◽  
Carney Complex ◽  
Cancer Cell Proliferation ◽  
Complex Patients ◽  
Associated Tumors ◽  
Kinase A

Context: Carney complex, a multiple neoplasia syndrome, characterized primarily by spotty skin pigmentation and a variety of endocrine and other tumors, is caused by mutations in PRKAR1A, the gene that codes for the RIα subunit of protein kinase A (PKA). PKA controls cell proliferation in many cell types. The cAMP analogue 8-Cl-adenosine (8-Cl-ADO) is thought to inhibit cancer cell proliferation. Objective: The objective of the study was to study the antiproliferative effects of 8-Cl-ADO on growth and proliferation in B-lymphocytes of Carney complex patients that have PKA defects and to determine whether 8-CL-ADO could be used as a therapeutic agent in the treatment of Carney complex-associated tumors. Design: We used a multiparametric approach (i.e. growth and proliferation assays, PKA, and PKA subunit assays, cAMP and 3H-cAMP binding assays, and apoptosis assays) to understand the growth and proliferative effects of 8-Cl-ADO on human B-lymphocytes. Results: 8-Cl-ADO inhibited proliferation, mainly through its intracellular transport and metabolism, which induced apoptosis. PKA activity, cAMP levels, and 3H-cAMP binding were increased or decreased, respectively, by 8-Cl-ADO, whereas PKA subunit levels were differentially affected. 8-Cl-ADO also inhibited proliferation induced by G protein-coupled receptors for isoproterenol and adenosine, as well as proliferation induced by tyrosine kinase receptors. Conclusions: 8-Cl-ADO in addition to unambiguously inhibiting proliferation and inducing apoptosis in a PKA-independent manner also has PKA-dependent effects that are unmasked by a mutant PRKAR1A. Thus, 8-Cl-ADO could serve as a therapeutic agent in patients with Carney complex-related tumors. 8-Cl-adenosine inhibits cancer cell proliferation, and induces apoptosis in B lymphocytes of Carney complex patients by PKA-independent and dependent effects that are unmasked by a mutant PRKAR1A.

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