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 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 Identification of microRNAs that Mediate Thyroid Cell Growth Induced by TSH

2012 ◽  
Vol 26 (3) ◽  
pp. 493-501 ◽  
Author(s):  
Takeshi Akama ◽  
Mariko Sue ◽  
Akira Kawashima ◽  
Huhehasi Wu ◽  
Kazunari Tanigawa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Protein Kinase ◽  
Cell Growth ◽  
Protein Kinase A ◽  
Target Genes ◽  
Endocrine Function ◽  
Thyroid Cell ◽  
Thyroid Cells ◽  
Kinase A

Abstract TSH is a major regulator of thyroid cell growth and endocrine function. It is known that cAMP and phosphatidylinositol 3-kinase (PI3K) are responsible for mediating the action of TSH. Activation of these signals results in the induction of a series of transcription factors and cell cycle regulating proteins, which induce cell proliferation. In addition to such canonical transcriptional regulation, it was recently shown that microRNA (miRNA or miR) constitutes another key mechanism for the regulation of gene expression. However, whether TSH action is mediated by miRNA in the thyroid is unknown. In this study, we have performed miRNA microarray analysis and demonstrated that TSH significantly decreases expression of 47 miRNA in thyroid cells. Among these, we have shown, using their specific agonists, that overexpression of miR-16 and miR-195 suppressed cell cycle progression and DNA synthesis that was induced by TSH. In silico analysis predicted that Mapk8, Ccne1, and Cdc6, the expression of which was up-regulated by TSH, are potential target genes for these miRNA, and overexpression of miR-16 and miR-195 suppressed expression of these target genes. The decrease of miR-16 and miR-195 expression by TSH was reproduced by forskolin and N6,2′-O-dibutyryladenosine cAMP and reversed by the protein kinase A inhibitor H89 and the PI3K inhibitor LY294002. These results suggest that TSH activates cAMP/protein kinase A and PI3K cascades to decrease miR-16 and miR-195, which induce Mapk8, Ccne1, and Cdc6 to activate cell proliferation.

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

Protein kinase A regulates cell cycle progression of mouse fertilized eggs by means of MPF

2004 ◽  
Vol 232 (1) ◽  
pp. 98-105 ◽  
Author(s):  
Bingzhi Yu ◽  
Yajie Wang ◽  
Ying Liu ◽  
Yi Liu ◽  
Xinna Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Kinase A

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.

scholarly journals Interference with 3′,5′-Cyclic Adenosine Monophosphate Response Element Binding Protein Stimulates Apoptosis through Aberrant Cell Cycle Progression and Checkpoint Activation

2006 ◽  
Vol 20 (5) ◽  
pp. 1112-1120 ◽  
Author(s):  
Jessica H. Dworet ◽  
Judy L. Meinkoth
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Survival ◽  
Protein Kinase A ◽  
Cell Cycle Progression ◽  
Thyroid Cell ◽  
Checkpoint Activation ◽  
Cycle Progression ◽  
Element Binding Protein ◽  
Kinase A

Abstract We previously reported that protein kinase A activity is an important determinant of thyroid cell survival. Given the important role of cAMP response element binding protein (CREB) in mediating the transcriptional effects of protein kinase A, we explored whether interference with CREB family members impaired thyroid cell survival. Expression of A-CREB, a dominant-negative CREB mutant that inhibits CREB DNA binding activity, induced apoptosis in rat thyroid cells. A-CREB inhibited CRE-regulated gene expression but failed to alter the expression of bcl-2 family members or of well-characterized inhibitors of apoptosis. To elucidate the mechanism through which impaired CREB function triggered apoptosis, its effects on cell proliferation were examined. Expression of A-CREB inhibited cell number increases, in part due to delayed cell cycle transit. Protracted S-phase progression in A-CREB-expressing cells was sufficient to activate a checkpoint response characterized by Chk-1, histone H2A.X, and p53 phosphorylation. To determine whether cell cycle progression was required for apoptosis, the effects of p27 overexpression were investigated. Overexpression of p27 prevented cell cycle progression, checkpoint activation, and apoptosis in A-CREB-expressing cells. These data reveal a novel mechanism through which interference with CREB abrogates cell survival, through checkpoint activation secondary to cell cycle delay. This study may explain how interference with CREB induces apoptosis in cells where alterations in the expression of pro- and anti-survival genes are not detected.

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