Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adrenal cancer is a rare neoplasm; however, up to 1 in 1 500 adrenal incidentalomas may hide a carcinoma, which, if diagnosed late or left untreated, is associated with significant morbidity and mortality. Despite extensive investigation of the molecular mechanisms involved in adrenal carcinogenesis and significant improvements in diagnostic imaging, efforts to cure advanced adrenal cancer remain largely unsuccessful. Thus, the investigation of the genetics of adrenocortical cancer by the candidate or positional cloning gene approach is essential in the development of new therapies for this disease. We propose that adrenocortical tumorigenesis follows a pattern similar to that in other organs: As the pathology of the adrenocortical tumor increases towards malignancy, the genetic changes that are observed also increase. Known genetic associations, like TP53 gene changes, occur during the latest stages of adrenocortical tumorigenesis. Thus, it is essential to study the relatively few genes that are affected at the beginning of this process, at the stages of benign tumorigenesis in the cortex. We have studied primary pigmented adrenocortical disease (PPNAD), a benign, bilateral, adrenocortical hyperplasia, which either in its isolated form or as part of Carney complex (CNC), is inherited in an autosomal dominant manner and, therefore, the gene(s) responsible for this disorder could be identified by positional cloning approaches. Indeed, we have identified two genetic loci harboring genes for PPNAD and/or CNC on chromosomal loci 2p16 and 17q22-24. The chromosome 17 gene, PRKAR1A, was recently cloned and the identification of other responsible genes is currently under way in our, and collaborating laboratories. The present report reviews the genetics of adrenocortical cancer first, followed by what is known today about the genetics of PPNAD and/or CNC.
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PMID:Genetics of adrenocortical tumors: Carney complex. 1135 91

The adrenal glands are a major source of steroid hormone biosynthesis. In normal physiology, the pituitary hormone corticotropin (ACTH) regulates the secretion of glucocorticoids via its G protein-coupled receptor (ACTHR), the product of the MC2R gene. Aldosterone is another major product of the adrenal gland; its regulation is controlled mainly by the renin-angiotensin system, although ACTH plays a role, too, especially under certain pathological conditions. The adrenal gland also secretes lesser amounts of androgens and intermediate metabolites of all these steroids. Unregulated secretion of any of these hormones can be caused by tumors, adrenocortical adenomas or carcinomas, and/or bilateral (or, rarely, unilateral) hyperplasia. Cortisol-producing hyperplasia of the adrenal glands is caused by two distinct syndromes, both of which have been directly or indirectly associated with protein kinase A signaling: (i) primary pigmented nodular adrenocortical disease (PPNAD) (a micronodular form of bilateral adrenal hyperplasia), either isolated (rarely) or in the context of Carney complex, is caused (in most cases) by mutations of the PRKAR1A gene; and (ii) ACTH-independent macronodular adrenal hyperplasia (AIMAH), or massive macronodular adrenal disease (MMAD), has been associated with aberrant (ectopic) expression, and presumably regulation, of various G protein-coupled receptors. AIMAH is a rare, sporadic condition affecting predominantly middle-aged men and women with an almost equal ratio (the latter in contrast to other forms of endogenous Cushing's syndrome). Some familial cases of AIMAH have also been described, and it appears that the pathophysiological phenomena underlying AIMAH may be present in the far more common, sporadic adrenocortical tumors and, perhaps, in the nodular growth detected in the adrenal glands of the elderly in the general population. Thus, the study of ectopic receptor expression and cAMP-dependent PKA activity in AIMAH may have wider implications for adrenal and, indeed, endocrine tumorigenesis.
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PMID:Cyclic AMP-dependent signaling aberrations in macronodular adrenal disease. 1211 80

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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PMID:Regulatory subunit type I-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer. 1220 83

We studied 11 new kindreds with primary pigmented nodular adrenocortical disease (PPNAD) or Carney complex (CNC) and found that 82% of the kindreds had PRKAR1A gene defects (including seven novel inactivating mutations), most of which led to nonsense mRNA and, thus, were not expressed in patients' cells. However, a previously undescribed base substitution in intron 6 (exon 6 IVS +1G-->T) led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent protein kinase A (PKA) signaling at the nuclear level. This is the first demonstration of an inactivating PRKAR1A mutation being expressed at the protein level and leading to stimulation of the PKA pathway in CNC patients. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggest that alteration of PRKAR1A function (not only its complete loss) is sufficient for augmenting PKA activity leading to tumorigenesis in tissues affected by CNC.
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PMID:Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. 1242 9

Carney complex (CNC) is a multiple endocrine neoplasia (MEN) syndrome characterized by lentigines, cardiac myxomas and tumors, including primary pigmented adrenocortical disease (PPNAD). In the present report we review the main clinical manifestations of this disorder. We also discuss some of the newest molecular information regarding CNC. The complex has been mapped to 2p16 and 17q22-24, and a third locus appears likely. The gene coding for the protein kinase A (PKA) type I-a regulatory subunit (RIa), PRKAR1A, had been mapped to 17q. Cloning of the PRKAR1A genomic structure and its sequencing showed mutations in CNC patients. So far, among 57 kindreds, PRKAR1A mutations have been found in 28. In almost all the mutations, the sequence change is predicted to lead to a premature stop codon; 1 mutation altered the initiator ATG codon. Analysis of mRNA transcripts in patient lymphocytes treated with cycloheximide showed that mutant mRNAs containing a premature stop codon were degraded, due to nonsense-mediated mRNA decay--the predicted mtPRKAR1A protein products were absent in these cells. In CNC tumors, PKA activity showed increased stimulation by cAMP, whereas PKA activity ratio was decreased. To date, mutations in the PRKAR1A gene have been described in CNC patients and in some sporadic endocrine tumors. LOH of the normal allele and increased PKA activity in response to cAMP are found in these tumors, suggesting that normal PRKAR1A (largely responsible for PKA type I activity) is implicated more widely in endocrine tumorigenesis. CNC is the first human disease caused by mutations of one of the subunits of the PKA holoenzyme, a critical component of numerous cellular signaling systems.
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PMID:Clinical and molecular genetics of Carney complex. 1266 84

Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia and lentiginosis syndrome characterised by spotty skin pigmentation, cardiac, skin, and breast myxomas, and a variety of endocrine and other tumours. The disease is genetically heterogeneous; two loci have been mapped to chromosomes 17q22-24 (the CNC1 locus) and 2p16 (CNC2). Mutations in the PRKAR1A tumour suppressor gene were recently found in CNC1 mapping kindreds, while the CNC2 and perhaps other genes remain unidentified. Analysis of tumour chromosome rearrangements is a useful tool for uncovering genes with a role in tumorigenesis and/or tumour progression. CGH analysis showed a low level 2p amplification recurrently in four of eight CNC tumours; one tumour showed specific amplification of the 2p16-p23 region only. To define more precisely the 2p amplicon in these and other tumours, we completed the genomic mapping of the CNC2 region, and analysed 46 tumour samples from CNC patients with and without PRKAR1A mutations by fluorescence in situ hybridisation (FISH) using bacterial artificial chromosomes (BACs). Consistent cytogenetic changes of the region were detected in 40 (87%) of the samples analysed. Twenty-four samples (60%) showed amplification of the region represented as homogeneously stained regions (HSRs). The size of the amplicon varied from case to case, and frequently from cell to cell in the same tumour. Three tumours (8%) showed both amplification and deletion of the region in their cells. Thirteen tumours (32%) showed deletions only. These molecular cytogenetic changes included the region that is covered by BACs 400-P-14 and 514-O-11 and, in the genetic map, corresponds to an area flanked by polymorphic markers D2S2251 and D2S2292; other BACs on the centromeric and telomeric end of this region were included in varying degrees. We conclude that cytogenetic changes of the 2p16 chromosomal region that harbours the CNC2 locus are frequently observed in tumours from CNC patients, including those with germline, inactivating PRKAR1A mutations. These changes are mostly amplifications of the 2p16 region, that overlap with a previously identified amplicon in sporadic thyroid cancer, and an area often deleted in sporadic adrenal tumours. Both thyroid and adrenal tumours constitute part of CNC indicating that the responsible gene(s) in this area may indeed be involved in both inherited and sporadic endocrine tumour pathogenesis and/or progression.
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PMID:Chromosome 2 (2p16) abnormalities in Carney complex tumours. 1267 98

A mouse protein that interacts with the peripheral-type benzodiazepine receptor (PBR) and cAMP-dependent protein kinase A (PKA) regulatory subunit RIalpha (PRKAR1A), named PBR and PKA-associated protein 7 (PAP7), was identified and shown to be involved in hormone-induced steroid biosynthesis. We report the identification of the human PAP7 gene, its expression pattern, genomic structure, and chromosomal mapping to 1q32-1q41. Human PAP7 is a 60-kDa protein highly homologous to the rodent protein. PAP7 is widely present in human tissues and highly expressed in seminal vesicles, pituitary, thyroid, pancreas, renal cortex, enteric epithelium, muscles, myocardium and in steroidogenic tissues, including the gonads and adrenal cortex. These tissues are also targets of Carney complex (CNC), a multiple neoplasia syndrome caused by germline inactivating PRKAR1A mutations (PRKAR1A-mut) and associated with primary pigmented nodular adrenocortical disease (PPNAD) and increased steroid synthesis. PAP7 and PRKAR1A expression were studied in PPNAD and in lymphoblasts from patients bearing PRKAR1A-mut. Like PRKAR1A, PAP7 was decreased in CNC lymphocytes and PPNAD nodules, but not in the surrounding cortex. These studies showed that, like in the mouse, human PAP7 is highly expressed in steroidogenic tissues, where it follows the pattern of PRKAR1A expression, suggesting that it participates in PRKAR1A-mediated tumorigenesis and hypercortisolism.
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PMID:Molecular cloning, chromosomal localization of human peripheral-type benzodiazepine receptor and PKA regulatory subunit type 1A (PRKAR1A)-associated protein PAP7, and studies in PRKAR1A mutant cells and tissues. 1269 76

Carney complex (CNC) is caused by PRKAR1A-inactivating mutations. PRKAR1A encodes the regulatory subunit type I-alpha (RIalpha) of the cAMP-dependent kinase (PKA) holoenzyme; how RIalpha insufficiency leads to tumorigenesis remains unclear. In many cells PKA inhibits the extracellular receptor kinase (ERK1/2) cascade of the mitogen-activated protein kinase (MAPK) pathway leading to inhibition of cell proliferation. We investigated whether the PKA-mediated inhibitory effect on ERK1/2 is affected in CNC cells that carry germline PRKAR1A mutations. PKA activity both at baseline and after stimulation with cAMP was augmented in cells carrying mutations. Quantitative message analysis showed that the main PKA subunits expressed were type I (RIalpha and RIbeta) but RIalpha was decreased in mutant cells. Immunoblot assays of ERK1/2 phosphorylation by the cell- and pathway-specific stimulant lysophosphatidic acid (LPA) showed activation of this pathway in a time- and concentration-dependent manner that was prevented by a specific inhibitor. There was a greater rate of growth in mutant cells; forskolin and isoproterenol inhibited LPA-induced ERK1/2 phosphorylation in normal but not in mutant cells. Forskolin inhibited LPA-induced cell proliferation and metabolism in normal cells, but stimulated these parameters in mutant cells. These data were also replicated in a pituitary tumor cell line carrying the most common PRKAR1A mutation (c.578del TG), and an in vitro construct of mutant PRKAR1A that was recently shown to lead to augmented PKA-mediated phosphorylation. We conclude that PKA activity in CNC cells is increased and that its stimulation by forskolin or isoproterenol increases LPA-induced ERK1/2 phosphorylation, cell metabolism and proliferation. Reversal of PKA-mediated inhibition of this MAPK pathway in CNC cells may contribute to tumorigenesis in this condition.
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PMID:Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2. 1281 76

Carney complex (CNC) is a multiple neoplasia syndrome that consists of endocrine (thyroid, pituitary, adrenocortical and gonadal), non-endocrine (myxomas, nevi and other cutaneous pigmented lesions), and neural (schwannomas) tumors. Primary pigmented nodular adrenocortical disease (PPNAD) is the most common endocrine manifestation of CNC and the only inherited form of Cushing syndrome known to date. In the search of genes responsible for CNC, two chromosomal loci were identified; one (17q22-24) harbored the gene encoding the type I-alpha regulatory subunit (RIalpha) of protein kinase A (PKA), PRKAR1A, a critical component of the cAMP signaling pathway. Here we review CNC and the implications of this discovery for the cAMP and/or PKA's involvement in human tumorigenesis.
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PMID:Human tumors associated with Carney complex and germline PRKAR1A mutations: a protein kinase A disease! 1282 37

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.
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PMID:Protein kinase A and its role in human neoplasia: the Carney complex paradigm. 1516 2


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