Anti-proliferative effects of 8-chloro-cAMP and other cAMP analogs are unrelated to their effects on protein kinase A regulatory subunit expression

2002 ◽  
Vol 192 (2) ◽  
pp. 216-224 ◽  
Author(s):  
Darija Lamb ◽  
Robert A. Steinberg
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Regulatory Subunit ◽  
Subunit Expression ◽  
Kinase A

scholarly journals PRKAR1A gene analysis and protein kinase A activity in endometrial tumors

2012 ◽  
Vol 19 (4) ◽  
pp. 457-462 ◽  
Author(s):  
A Tsigginou ◽  
E Bimpaki ◽  
M Nesterova ◽  
A Horvath ◽  
S Boikos ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Regulatory Subunit ◽  
Normal Endometrium ◽  
Protein Levels ◽  
Normal Tissues ◽  
Subunit Expression ◽  
Dependent Protein ◽  
Pka Regulatory Subunit ◽  
Kinase A

PRKAR1A codes for the type 1a regulatory subunit (RIα) of the cAMP-dependent protein kinase A (PKA), an enzyme with an important role in cell cycle regulation and proliferation. PKA dysregulation has been found in various tumors, and PRKAR1A-inactivating mutations have been reported in mostly endocrine neoplasias. In this study, we investigated PKA activity and the PRKAR1A gene in normal and tumor endometrium. Specimens were collected from 31 patients with endometrial cancer. We used as controls 41 samples of endometrium that were collected from surrounding normal tissues or from women undergoing gynecological operations for other reasons. In all samples, we sequenced the PRKAR1A-coding sequence and studied PKA subunit expression; we also determined PKA activity and cAMP binding. PRKAR1A mutations were not found. However, PKA regulatory subunit protein levels, both RIα and those of regulatory subunit type 2b (RIIβ), were lower in tumor samples; cAMP binding was also lower in tumors compared with normal endometrium (P<0.01). Free PKA activity was higher in tumor samples compared with that of control tissue (P<0.01). There are significant PKA enzymatic abnormalities in tumors of the endometrium compared with surrounding normal tissue; as these were not due to PRKAR1A mutations, other mechanisms affecting PKA function ought to be explored.

scholarly journals 17q22–24 Chromosomal Losses and Alterations of Protein Kinase A Subunit Expression and Activity in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia

2006 ◽  
Vol 91 (9) ◽  
pp. 3626-3632 ◽  
Author(s):  
Isabelle Bourdeau ◽  
Ludmila Matyakhina ◽  
Sotirios G. Stergiopoulos ◽  
Fabiano Sandrini ◽  
Sosipatros Boikos ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing Syndrome ◽  
Carney Complex ◽  
Chromosome 17 ◽  
Regulatory Subunit ◽  
Adrenal Tumors ◽  
Adrenal Hyperplasia ◽  
Subunit Expression ◽  
Kinase A

Abstract Context: Primary adrenocortical hyperplasias leading to Cushing syndrome include primary pigmented nodular adrenocortical disease and ACTH-independent macronodular adrenal hyperplasia (AIMAH). Inactivating mutations of the 17q22–24-located PRKAR1A gene, coding for the type 1A regulatory subunit of protein kinase A (PKA), cause primary pigmented nodular adrenocortical disease and the multiple endocrine neoplasia syndrome Carney complex. PRKAR1A mutations and 17q22–24 chromosomal losses have been found in sporadic adrenal tumors and are associated with aberrant PKA signaling. Objective: The objective of the study was to examine whether somatic 17q22–24 changes, PRKAR1A mutations, and/or PKA abnormalities are present in AIMAH. Patients: We studied fourteen patients with Cushing syndrome due to AIMAH. Methods: Fluorescent in situ hybridization with a PRKAR1A-specific probe was used for investigating chromosome 17 allelic losses. The PRKAR1A gene was sequenced in all samples, and tissue was studied for PKA activity, cAMP responsiveness, and PKA subunit expression. Results: We found 17q22–24 allelic losses in 73% of the samples. There were no PRKAR1A-coding sequence mutations. The RIIβ PKA subunit was overexpressed by mRNA, whereas the RIα, RIβ, RIIα, and Cα PKA subunits were underexpressed. These findings were confirmed by immunohistochemistry. Total PKA activity and free PKA activity were higher in AIMAH than normal adrenal glands, consistent with the up-regulation of the RIIβ PKA subunit. Conclusions: PRKAR1A mutations are not found in AIMAH. Somatic losses of the 17q22–24 region and PKA subunit and enzymatic activity changes show that PKA signaling is altered in AIMAH in a way that is similar to that of other adrenal tumors with 17q losses or PRKAR1A mutations.

scholarly journals Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa

1994 ◽  
Vol 69 (4) ◽  
pp. 738-742 ◽  
Author(s):  
AW Bradbury ◽  
DC Carter ◽  
WR Miller ◽  
YS Cho-Chung ◽  
T Clair
Keyword(s):  
Colorectal Cancer ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Regulatory Subunit ◽  
Subunit Expression ◽  
Kinase A

scholarly journals Targeting the Regulatory Subunit R2Alpha of Protein Kinase A in Human Glioblastoma through shRNA-Expressing Lentiviral Vectors

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1361
Author(s):  
Maira Zorzan ◽  
Claudia Del Vecchio ◽  
Stefania Vogiatzis ◽  
Elisa Saccon ◽  
Cristina Parolin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Lentiviral Vectors ◽  
Brain Parenchyma ◽  
Regulatory Subunit ◽  
Glioblastoma Cells ◽  
Cellular Models ◽  
Therapeutic Setting ◽  
Promising Target ◽  
Kinase A

Glioblastoma is the most malignant and most common form of brain tumor, still today associated with a poor 14-months median survival from diagnosis. Protein kinase A, particularly its regulatory subunit R2Alpha, presents a typical intracellular distribution in glioblastoma cells compared to the healthy brain parenchyma and this peculiarity might be exploited in a therapeutic setting. In the present study, a third-generation lentiviral system for delivery of shRNA targeting the regulatory subunit R2Alpha of protein kinase A was developed. Generated lentiviral vectors are able to induce an efficient and stable downregulation of R2Alpha in different cellular models, including non-stem and stem-like glioblastoma cells. In addition, our data suggest a potential correlation between silencing of the regulatory subunit of protein kinase A and reduced viability of tumor cells, apparently due to a reduction in replication rate. Thus, our findings support the role of protein kinase A as a promising target for novel anti-glioma therapies.

The crystal structure of yeast regulatory subunit reveals key evolutionary insights into Protein Kinase A oligomerization

2021 ◽  
pp. 107732
Author(s):  
Nicolás González Bardeci ◽  
Enzo Tofolón ◽  
Felipe Trajtenberg ◽  
Julio Caramelo ◽  
Nicole Larrieux ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Regulatory Subunit ◽  
Kinase A

Overexpression of the regulatory subunit of protein kinase A increases heterologous protein expression in Pichia pastoris

2020 ◽  
Vol 42 (12) ◽  
pp. 2685-2692 ◽  
Author(s):  
Xihao Liao ◽  
Wenyang Lin ◽  
Nanzhu Chen ◽  
Lu Li ◽  
Dafu Huang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Pichia Pastoris ◽  
Protein Expression ◽  
Protein Kinase A ◽  
Heterologous Protein ◽  
Regulatory Subunit ◽  
Heterologous Protein Expression ◽  
Kinase A

scholarly journals The Role of Uncoupling Protein 1 in the Metabolism and Adiposity of RIIβ-Protein Kinase A-Deficient Mice

2004 ◽  
Vol 18 (9) ◽  
pp. 2302-2311 ◽  
Author(s):  
Michael A. Nolan ◽  
Maria A. Sikorski ◽  
G. Stanley McKnight
Keyword(s):  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Uncoupling Protein ◽  
Mrna Level ◽  
Regulatory Subunit ◽  
Uncoupling Protein 1 ◽  
Brown Adipose ◽  
Kinase A

Abstract Mice lacking the RIIβ regulatory subunit of protein kinase A exhibit a 50% reduction in white adipose tissue stores compared with wild-type littermates and are resistant to diet-induced obesity. RIIβ−/− mice also have an increase in resting oxygen consumption along with a 4-fold increase in the brown adipose-specific mitochondrial uncoupling protein 1 (UCP1). In this study, we examined the basis for UCP1 induction and tested the hypothesis that the induced levels of UCP1 in RIIβ null mice are essential for the lean phenotype. The induction of UCP1 occurred at the protein but not the mRNA level and correlated with an increase in mitochondria in brown adipose tissue. Mice lacking both RIIβ and UCP1 (RIIβ−/−/Ucp1−/−) were created, and the key parameters of metabolism and body composition were studied. We discovered that RIIβ−/− mice exhibit nocturnal hyperactivity in addition to the increased oxygen consumption at rest. Disruption of UCP1 in RIIβ−/− mice reduced basal oxygen consumption but did not prevent the nocturnal hyperactivity. The double knockout animals also retained the lean phenotype of the RIIβ null mice, demonstrating that induction of UCP1 and increased resting oxygen consumption is not the cause of leanness in the RIIβ mutant mice.

scholarly journals Complex effects of kinase localization revealed by compartment-specific regulation of protein kinase A activity

2021 ◽  
Author(s):  
Rebecca LaCroix ◽  
Benjamin Lin ◽  
Andre Levchenko
Keyword(s):  
Cell Migration ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Kinase Activity ◽  
Single Cells ◽  
Regulatory Subunit ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Specific Regulation ◽  
Kinase A

SummaryKinase activity in signaling networks frequently depends on regulatory subunits that can both inhibit activity by interacting with the catalytic subunits and target the kinase to distinct molecular partners and subcellular compartments. Here, using a new synthetic molecular interaction system, we show that translocation of a regulatory subunit of the protein kinase A (PKA-R) to the plasma membrane has a paradoxical effect on the membrane kinase activity. It can both enhance it at lower translocation levels, even in the absence of signaling inputs, and inhibit it at higher translocation levels, suggesting its role as a linker that can both couple and decouple signaling processes in a concentration-dependent manner. We further demonstrate that superposition of gradients of PKA-R abundance across single cells can control the directionality of cell migration, reversing it at high enough input levels. Thus complex in vivo patterns of PKA-R localization can drive complex phenotypes, including cell migration.

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