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 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.

scholarly journals Protein Kinase A-mediated Serine 35 Phosphorylation Dissociates Histone H1.4 from Mitotic Chromosome

2011 ◽  
Vol 286 (41) ◽  
pp. 35843-35851 ◽  
Author(s):  
Chi-Shuen Chu ◽  
Pang-Hung Hsu ◽  
Pei-Wen Lo ◽  
Elisabeth Scheer ◽  
Laszlo Tora ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cell Cycle Progression ◽  
Mass Spectrometry Analysis ◽  
Cycle Progression ◽  
Spectrometry Analysis ◽  
H3 Phosphorylation ◽  
Substitution Mutant ◽  
Kinase A ◽  
Mitotic Chromatin

Global histone H1 phosphorylation correlates with cell cycle progression. However, the function of site-specific H1 variant phosphorylation remains unclear. Our mass spectrometry analysis revealed a novel N-terminal phosphorylation of the major H1 variant H1.4 at serine 35 (H1.4S35ph), which accumulates at mitosis immediately after H3 phosphorylation at serine 10. Protein kinase A (PKA) was found to be a kinase for H1.4S35. Importantly, Ser-35-phosphorylated H1.4 dissociates from mitotic chromatin. Moreover, H1.4S35A substitution mutant cannot efficiently rescue the mitotic defect following H1.4 depletion, and inhibition of PKA activity increases the mitotic chromatin compaction depending on H1.4. Our results not only indicate that PKA-mediated H1.4S35 phosphorylation dissociates H1.4 from mitotic chromatin but also suggest that this phosphorylation is necessary for specific mitotic functions.

scholarly journals Control of metaphase–anaphase progression by proteolysis: cyclosome function regulated by the protein kinase A pathway, ubiquitination and localization

1999 ◽  
Vol 354 (1389) ◽  
pp. 1559-1570 ◽  
Author(s):  
M. Yanagida ◽  
Y. M. Yamashita ◽  
H. Tatebe ◽  
K. Ishii ◽  
K. Kumada ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cellular Localization ◽  
Cell Cycle Progression ◽  
Anaphase Promoting Complex ◽  
Cycle Arrest ◽  
Mitotic Cyclin ◽  
Functional Regulation ◽  
Kinase A

Ubiquitin–mediated proteolysis is fundamental to cell cycle progression. In the fission yeast Schizosaccharomyces pombe , a mitotic cyclin (Cdc13), a key cell cycle regulator, is degraded for exiting mitosis, while Cut2 has to be destroyed for the onset of sister chromatid separation in anaphase. Ubiquitination of these proteins requires the special destruction box (DB) sequences locating in their N–termini and the large, 20S complex called the anaphase–promoting complex or cyclosome. Here we show that cyclosome function during metaphase–anaphase progression is regulated by the protein kinase A (PKA) inactivation pathway, ubiquitination of the cyclosome subunit, and cellular localization of the target substrates. Evidence is provided that the cyclosome plays pleiotropic roles in the cell cycle: mutations in the subunit genes show a common anaphase defect, but subunit–specific phenotypes such as in G1/S or G2/M transition, septation and cytokinesis, stress response and heavy metal sensitivity, are additionally produced, suggesting that different subunits take distinct parts of complex cyclosome functions. Inactivation of PKA is important for the activation of the cyclosome for promoting anaphase, perhaps through dephosphorylation of the subunits such as Cut9 (Apc6). Cut4 (Apc1), the largest subunit, plays an essential role in the assembly and functional regulation of the cyclosome in response to cell cycle arrest and stresses. Cut4 is highly modified, probably by ubiquitination, when it is not assembled into the 20S cyclosome. Sds23 is implicated in DB–mediated ubiquitination possibly through regulating de–ubiquitination, while Cut8 is necessary for efficient proteolysis of Cdc13 and Cut2 coupled with cytokinesis. Unexpectedly, the timing of proteolysis is dependent on cellular localization of the substrate. Cdc13 enriched along the spindle disappears first, followed by decay of the nuclear signal, whereas Cut2 in the nucleus disappears first, followed by decline in the spindle signal during metaphase–anaphase progression.

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 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 The second phase activation of protein kinase C δ at late G1 is required for DNA synthesis in serum-induced cell cycle progression

2003 ◽  
Vol 8 (4) ◽  
pp. 311-324 ◽  
Author(s):  
Koichi Kitamura ◽  
Keiko Mizuno ◽  
Akiko Etoh ◽  
Yoshiko Akita ◽  
Akitomo Miyamoto ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Dna Synthesis ◽  
Cell Cycle Progression ◽  
Second Phase ◽  
Cycle Progression ◽  
Kinase C
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