scholarly journals Protein kinase A in Carney complex: a new example of cAMP pathway alteration in endocrine tumors

2001 ◽  
pp. 209-211 ◽  
Author(s):  
J Bertherat
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Carney Complex ◽  
Endocrine Tumors ◽  
Camp Pathway ◽  
Kinase A

scholarly journals Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity.

2008 ◽  
Vol 158 (6) ◽  
pp. 829-839 ◽  
Author(s):  
C Vincent-Dejean ◽  
L Cazabat ◽  
L Groussin ◽  
K Perlemoine ◽  
G Fumey ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Carney Complex ◽  
Catalytic Subunits ◽  
Regulatory Subunits ◽  
Adrenocortical Tumors ◽  
Camp Pathway ◽  
Adrenocortical Adenomas ◽  
Pka Pathway ◽  
Kinase A

ObjectiveThe cAMP/protein kinase A (PKA) pathway plays an important role in endocrine tumorigenesis. PKA is a heterotetramer with two regulatory subunits (four genes:PRKAR1A,PRKAR1B,PRKAR2A,PRKAR2B) and two catalytic subunits. InactivatingPRKAR1Amutations have been observed in Carney complex and a subset of adrenocortical tumors (ACT). This study was designed to search for other alterations of PKA in ACT, and to establish their correlation with the clinical characteristics.MethodsIn this study, 35 ACT (10 non-secreting adrenocortical adenomas (ACA-NS), 13 cortisol-secreting adenomas (ACA-S), and 12 malignant s (ACC)) were studied. PKA subunits were studied by western blot and RT-qPCR. The PKA activity was measured.ResultsA subgroup of ACA-S with a 96% R2B protein decrease by comparison with normal adrenal (4.1%±4 vs 100%±19,P<0.001) was identified, ACA-S2 (6/13). By contrast, no differences were observed in ACC and ACA-NS. The level of R1A mRNA was decreased in ACA-S (P<0.001), but not the level of R2B mRNA. No mutation of the R2B gene was detected in ACA-S2. The ACA-S2 group with loss of R2B protein showed a threefold higher basal PKA activity than the ACA with normal R2B protein (3.37±0.31 vs 1.00±0.20,P<0.0001). The ACA-S2 tumors with the loss of the R2B protein presented a homogenous phenotype and were all small benign cortisol-secreting tumors.ConclusionThis loss of PRKAR2B protein due to a post-transcriptional mechanism in ACA-S is a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis. It defines a new subtype of secreting adenomas with high basal PKA activity presenting a homogenous clinical phenotype.

scholarly journals Carney Complex

2018 ◽  
Vol 127 (02/03) ◽  
pp. 156-164 ◽  
Author(s):  
Crystal Kamilaris ◽  
Fabio Faucz ◽  
Antonis Voutetakis ◽  
Constantine Stratakis
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Multiple Endocrine Neoplasia ◽  
Autosomal Dominant ◽  
Cushing Syndrome ◽  
Carney Complex ◽  
Regulatory Subunit ◽  
Endocrine Tumors ◽  
Skin Abnormalities ◽  
Kinase A

AbstractCarney complex is a rare, autosomal dominant, multiple endocrine neoplasia and lentiginosis syndrome, caused in most patients by defects in the PRKAR1A gene, which encodes the regulatory subunit type 1α of protein kinase A. Inactivating defects of PRKAR1A lead to aberrant cyclic-AMP-protein kinase A signaling. Patients may develop multiple skin abnormalities and a variety of endocrine and non-endocrine tumors. Endocrine manifestations include primary pigmented nodular adrenocortical disease, that may cause Cushing syndrome, growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia which can result in acromegaly, as well as gonadal and thyroid tumors. Non-endocrine tumors associated with Carney complex include myxomas of the heart, breast, and other sites, psamommatous melanotic schwannomas, breast ductal adenomas, osteochondromyxomas, and a predisposition to a number of malignancies from adrenal to pancreatic and liver cancer.

Protein Kinase A Alterations in Endocrine Tumors

2012 ◽  
Vol 44 (10) ◽  
pp. 741-748 ◽  
Author(s):  
B. Yu ◽  
B. Ragazzon ◽  
M. Rizk-Rabin ◽  
J. Bertherat
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Endocrine Tumors ◽  
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.

Protein kinase A and its role in human neoplasia: the Carney complex paradigm.

2004 ◽  
Vol 11 (2) ◽  
pp. 265-280 ◽  
Author(s):  
I Bossis ◽  
A Voutetakis ◽  
T Bei ◽  
F Sandrini ◽  
K J Griffin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing Syndrome ◽  
Skin Pigmentation ◽  
Suppressor Gene ◽  
Carney Complex ◽  
Regulatory Subunit ◽  
Extensive Literature ◽  
Bilateral Adrenal Hyperplasia ◽  
Kinase A

The type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PKA) (PRKAR1A) is an important regulator of the serine-threonine kinase activity catalyzed by the PKA holoenzyme. Carney complex (CNC) describes the association 'of spotty skin pigmentation, myxomas, and endocrine overactivity'; CNC is in essence the latest form of multiple endocrine neoplasia to be described and affects the pituitary, thyroid, adrenal and gonadal glands. Primary pigmented nodular adrenocortical disease (PPNAD), a micronodular form of bilateral adrenal hyperplasia that causes a unique, inherited form of Cushing syndrome, is also the most common endocrine manifestation of CNC. CNC and PPNAD are genetically heterogeneous but one of the responsible genes is PRKAR1A, at least for those families that map to 17q22-24 (the chromosomal region that harbors PRKAR1A). CNC and/or PPNAD are the first human diseases to be caused by mutations in one of the subunits of the PKA holoenzyme. Despite the extensive literature on R1alpha and PKA, little is known about their potential involvement in cell cycle regulation, growth and/or proliferation. The presence of inactivating germline mutations and the loss of its wild-type allele in CNC lesions indicated that PRKAR1A could function as a tumor-suppressor gene in these tissues. However, there are conflicting data in the literature about PRKAR1A's role in human neoplasms, cancer cell lines and animal models. In this report, we review briefly the genetics of CNC and focus on the involvement of PRKAR1A in human tumorigenesis in an effort to reconcile the often diametrically opposite reports on R1alpha.

scholarly journals Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

2021 ◽  
Vol 131 (23) ◽  
Author(s):  
Cyril Djari ◽  
Isabelle Sahut-Barnola ◽  
Amandine Septier ◽  
Ingrid Plotton ◽  
Nathanaëlle Montanier ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Carney Complex ◽  
Testis Tumor ◽  
Kinase A

scholarly journals PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A

2020 ◽  
Vol 27 (11) ◽  
pp. 647-656
Author(s):  
Stephanie Espiard ◽  
Ludivine Drougat ◽  
Nikolaos Settas ◽  
Sara Haydar ◽  
Kerstin Bathon ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Stability ◽  
Protein Kinase A ◽  
De Novo ◽  
Carney Complex ◽  
Functional Studies ◽  
Skeletal Disease ◽  
Skeletal Defects ◽  
Adrenocortical Hyperplasia ◽  
Kinase A

Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.

scholarly journals Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations

2021 ◽  
Vol 118 (21) ◽  
pp. e2024716118
Author(s):  
Naeimeh Jafari ◽  
Jason Del Rio ◽  
Madoka Akimoto ◽  
Jung Ah Byun ◽  
Stephen Boulton ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Molecular Mechanisms ◽  
Carney Complex ◽  
Regulatory Subunit ◽  
Regulatory Subunits ◽  
Inhibitory Function ◽  
Wide Range ◽  
Liver Cancers ◽  
Kinase A

Familial mutations of the protein kinase A (PKA) R1α regulatory subunit lead to a generalized predisposition for a wide range of tumors, from pituitary adenomas to pancreatic and liver cancers, commonly referred to as Carney complex (CNC). CNC mutations are known to cause overactivation of PKA, but the molecular mechanisms underlying such kinase overactivity are not fully understood in the context of the canonical cAMP-dependent activation of PKA. Here, we show that oligomerization-induced sequestration of R1α from the catalytic subunit of PKA (C) is a viable mechanism of PKA activation that can explain the CNC phenotype. Our investigations focus on comparative analyses at the level of structure, unfolding, aggregation, and kinase inhibition profiles of wild-type (wt) PKA R1α, the A211D and G287W CNC mutants, as well as the cognate acrodysostosis type 1 (ACRDYS1) mutations A211T and G287E. The latter exhibit a phenotype opposite to CNC with suboptimal PKA activation compared with wt. Overall, our results show that CNC mutations not only perturb the classical cAMP-dependent allosteric activation pathway of PKA, but also amplify significantly more than the cognate ACRDYS1 mutations nonclassical and previously unappreciated activation pathways, such as oligomerization-induced losses of the PKA R1α inhibitory function.

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