Mutation analysis of protein kinase A catalytic subunit in thyroid adenomas and pituitary tumours

Esapa, C; Harris, PE

doi:10.1530/eje.0.1410409

Cited by 24 publications

(17 citation statements)

References 22 publications

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“…In this case, the R2B/ Ca ratio would favor an increased PKA activity. Esapa et al also observed that an alteration of the catalytic subunit of PKA is detected neither in thyroid tumors nor in pituitary adenomas (34). The tendency for a decreased level of R2A and R1A proteins in the ACA-S2 group might also take part in this stimulation of basal PKA activity.…”

Section: European Journal Of Endocrinology (2008) 158mentioning

confidence: 96%

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.

Vincent-Dejean

Cazabat

Groussin

et al. 2008

European Journal of Endocrinology

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Objective: The 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. Inactivating PRKAR1A mutations 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. Methods: In this study, 35 ACT (10 non-secreting adrenocortical adenomas (ACA-NS), 13 cortisolsecreting 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. Results: A subgroup of ACA-S with a 96% R2B protein decrease by comparison with normal adrenal (4.1%G4 vs 100%G19, 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 (3.37G0.31 vs 1.00G0.20, 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. Conclusion: This 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.European Journal of Endocrinology 158 829-839

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Section: European Journal Of Endocrinology (2008) 158mentioning

confidence: 96%

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.

Vincent-Dejean

Cazabat

Groussin

et al. 2008

European Journal of Endocrinology

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“…A part of area including codon 196 of the PKA gene was amplified using primers and PCR conditions as described by Esapa and Harris [9].…”

Section: Polymerase Chain Reaction (Pcr)mentioning

confidence: 99%

“…PKA consists of two regulatory (R) and two catalytic (C) subunits. When two cAMP molecules bind to the R subunit, active C subunits are released and enter the nucleus where they phosphorylate CREB, which is involved in the transcription regulation process [7,9]. Therefore, both thyroid growth and function are regulated by cAMP-PI 3 [5].…”

mentioning

confidence: 99%

“…Thus research into the signal transduction pathways downstream of the G proteins became important [8]. Based on this theory, a part of the gene of the catalytic subunit of the PKA was also screened for mutations in thyroid nodules [9]. Catalytic (C) subgroup mutants of PKA were first identified in 1992 [23].…”

mentioning

confidence: 99%

“…It was thought that they were involved in the pathogenesis of thyroid nodules. Therefore, a part of the gene of the catalytic subunit of PKA was also screened for mutations in thyroid nodules, but none was detected [9].…”

mentioning

confidence: 99%

See 2 more Smart Citations

Mutations in the Thyrotropin Receptor Signal Transduction Pathway in the Hyperfunctioning Thyroid Nodules from Multinodular Goiters: A Study in the Turkish Population

et al. 2005

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Abstract. Many studies have been carried out to determine G s a and TSHR mutations in autonomously functioning thyroid nodules. Variable prevalences for somatic constitutively activating TSHR mutations in hot nodules have been reported. Moreover, the increased prevalence of toxic multinodular goiters in iodine-deficient regions is well known. In Turkey, a country with high incidence rates of goiter due to iodine deficiency, the frequency of mutations in the thyrotropin receptor signal transduction pathway has not been evaluated up to now. In the present study, a part of the genes of the TSHR, G s a and the catalytic subunit of the PKA were checked for activating mutations. Thirty-five patients who underwent thyroidectomy for multinodular goiters were examined. Genomic DNAs were extracted from 58 hyperactive nodular specimens and surrounding normal thyroid tissues. Mutation screening was done by single-strand conformational polymorphism (SSCP) analysis. In those cases where a mutation was detected, the localization of the mutation was determined by automatic DNA sequencing. No G s a or PKA mutations were detected, whereas ten mutations (17%) were identified in the TSHR gene. All mutations were somatic and heterozygotic. In conclusion, the frequency of mutations in the cAMP signal transduction pathway was found to be lower than expected in the Turkish population most likely because of the use of SSCP as a screening method and sequencing only a part of TSHR exon 10.

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Regulatory subunit type I‐α of protein kinase A (PRKAR1A): A tumor‐suppressor gene for sporadic thyroid cancer

Sandrini

Matyakhina

Sarlis

et al. 2002

Genes Chromosomes & Cancer

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The tumor-suppressor gene encoding the cyclic AMP-dependent protein kinase A type I-alpha regulatory subunit PRKAR1A has been mapped to chromosome 17 (17q22-24) and is mutated in Carney complex, a familial neoplasia syndrome that is associated with thyroid tumors. Other genes implicated in cyclic nucleotide-dependent signaling have been investigated in thyroid tumorigenesis. We studied protein kinase A (PKA) activity in noninherited follicular thyroid adenomas and follicular, papillary, and undifferentiated (anaplastic) thyroid carcinomas. We then examined these and additional thyroid tumors for losses of the 17q22-24 PRKAR1A region, mutations of the PRKAR1A gene, and expression of its peptide product. Total PKA activity was markedly increased in carcinomas over that in adenomas, whereas the ratio of free vs. total PKA activity was decreased in cancer. Consistent with these findings, the 17q22-24 region was frequently lost in cancer but not in benign adenomas. A novel inactivating mutation of the PRKAR1A gene (leading to premature termination of the predicted protein) was found in an aggressive thyroid cancer. The tumor with PRKAR1A gene mutation, as well as the tumors with 17q allelic losses, showed decreased PRKAR1A expression by immunostaining. We conclude that PRKAR1A, the most abundant regulatory subunit of protein kinase A and a principal cyclic AMP-signaling modulator, acts as a tumor-suppressor gene in sporadic thyroid cancer. Published 2002 Wiley-Liss, Inc.

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Mutation analysis of protein kinase A catalytic subunit in thyroid adenomas and pituitary tumours

Cited by 24 publications

References 22 publications

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.

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.

Mutations in the Thyrotropin Receptor Signal Transduction Pathway in the Hyperfunctioning Thyroid Nodules from Multinodular Goiters: A Study in the Turkish Population

Regulatory subunit type I‐α of protein kinase A (PRKAR1A): A tumor‐suppressor gene for sporadic thyroid cancer

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