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PubMed · 15331577

Minireview: PRKAR1A: normal and abnormal functions.

Ioannis Bossis·Constantine A Stratakis
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Abstract

The type 1alpha regulatory subunit (RIalpha) of cAMP-dependent protein kinase (PKA) (coded by the PRKAR1A gene) is the main component of type I PKA, which regulates most of the serine-threonine kinase activity catalyzed by the PKA holoenzyme in response to cAMP. Carney complex (CNC), or the complex of spotty skin pigmentation, myxomas, and endocrine overactivity, is a multiple endocrine (and not only) neoplasia syndrome that is due to PRKAR1A-inactivating mutations. The R1alpha protein and PRKAR1A mRNA have been found to be up-regulated in a series of cell lines and human and rodent neoplasms, suggesting this molecule's involvement in tumorigenesis and its potential role in cell cycle regulation, growth, and/or proliferation. Alterations in PKA activity elicit a variety of effects depending on the tissue, developmental stage, degree of differentiation, and cAMP levels. In addition, RIalpha may have functions independent of PKA. The presence of inactivating germline mutations and the loss of its wild-type allele in some CNC lesions indicate that PRKAR1A might function as a tumor suppressor gene in these tissues, but could PRKAR1A be a classic tumor suppressor gene? Probably not, and this review explains why.

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Cyclic AMP-Dependent Protein Kinase RIalpha SubunitCyclic AMP-Dependent Protein KinasesEndocrine System DiseasesHumansMyxomaPigmentation DisordersProteinsSoft Tissue NeoplasmsJournal ArticleReview

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Ioannis Bossis, Constantine A Stratakis. 2004-08-26. Minireview: PRKAR1A: normal and abnormal functions.. https://doi.org/10.1210/en.2004-0900

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PubMed2006

[Clinical features and pathogenesis of Carney complex, a rare form of multiple endocrine neoplasia syndromes].

Carney-complex is the rarest and most recently described form of multiple endocrine neoplasia syndromes that is unique both from clinical and pathogenetic aspects. Clinical features include spotty skin pigmentation, cutaneous and cardiac myxomas, multiple endocrine abnormalities and schwannomas. The most characteristic endocrine abnormality is primary pigmented nodular adrenal hyperplasia that may result in clinically apparent Cushing's syndrome. Acromegaly, hyperprolactinaemia, tumours of the testis and ovaries have also been described. Approximately fifty percent of Carney-complex cases are familial, with an autosomal dominant inheritance pattern. About 45-65% of Carney-complex cases are related to mutations of the PRKAR1A gene encoding a regulatory subunit of protein kinase A, but other genetic mechanisms seem to be involved, as well. Here, the authors present a brief synopsis of its clinical and pathogenetical features.

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PubMed2005

Molecular and immunohistochemical investigation of protein kinase a regulatory subunit type 1A (PRKAR1A) in odontogenic myxomas.

Odontogenic myxomas are rare benign neoplasms affecting the jaw. Myxomas of bones and other sites occur as part of Carney complex (CNC), a multiple neoplasia syndrome caused by mutations in the PRKAR1A gene, which codes for the regulatory subunit of protein kinase A (PKA). In the present study, 17 odontogenic myxomas from patients without CNC were screened for PRKAR1A mutations and PRKAR1A protein expression by immunohistochemistry (IHC). Mutations of the coding region of the PRKAR1A gene were identified in 2 tumors; both these lesions showed no or significantly decreased immunostaining of PRKAR1A in the tumor compared to that in the surrounding normal tissue. One mutation (c.725C>A) led to a nonconservative amino acid substitution in a highly conserved area of the gene (A213D); the other was a single base-pair deletion that led to a frameshift (del774C) and a stop codon 11 amino acids downstream of the mutation site; both tumors were heterozygous for the respective mutations. Of the remaining tumors, 7 of the 15 without mutations showed almost no PRKAR1A in the tumor cells, whereas IHC showed that the protein was abundant in nontumorous cells. We concluded that PRKAR1A may be involved by its down-regulation in the pathogenesis of odontogenic myxomas caused by mutations and/or other genetic mechanisms. Of the sporadic, nonfamilial tumors associated with PRKAR1A mutations, the odontogenic type was the first myxomatous lesion found to harbor somatic PRKAR1A sequence changes.

Cyclic AMP-Dependent Protein Kinase RIalpha Subuni↗
PubMed2004

Pathology and molecular genetics of the pituitary gland in patients with the 'complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas' (Carney complex).

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome with features overlapping those of McCune-Albright syndrome (MAS) and other multiple endocrine neoplasia (MEN) syndromes like MEN type 1 (MEN 1). Pituitary tumors have been described in a number of patients with CNC; all have been growth hormone (GH) and prolactin (PRL)-producing. In at least some patients, pituitary gland involvement is manifested by hyperplastic areas; hyperplasia appears to involve somatomammotrophs only and to precede GH-producing tumor formation, in a pathway similar to that seen in MAS-related pituitary tumors (and in oncogenesis in other CNC tissues). One patient with CNC and advanced acromegaly had a GH-producing macroadenoma that showed extensive genetic changes at the chromosomal level. These changes appeared to represent secondary or tertiary genetic 'hits' involved in pituitary oncogenesis and were confirmed at the molecular level. So far, almost half of the patients with CNC have germline-inactivating mutations in the PRKAR1A gene; in their pituitary tumors, the normal allele of the PRKAR1A gene is lost. Loss of heterozygosity suggests that PRKAR1A, which codes for the regulatory subunit type 1alpha of the cAMP-dependent protein kinase A (PKA), may act as a tumor-suppressor gene in pituitary tissue. These data provide evidence for a PKA-induced somatomammotroph hyperplasia in the pituitary tissue of CNC patients; hyperplasia leads to additional genetic changes at the somatic level, which in turn cause the formation of adenomas in some, but not all, patients.

Cyclic AMP-Dependent Protein Kinase RIalpha Subuni↗