Sequence analysis of the <i>PRKAR1A</i> gene in sporadic somatotroph and other pituitary tumours

Kaltsas, Gregory; Kola, Blerina; Borboli, Ninetta; Morris, Damian; Gueorguiev, Maria; Swords, FM; Czirják, Sándor; Kirschner, Lawrence S.; Stratakis, Constantine A.; Korbonits, Márta; Grossman, Ashley

doi:10.1046/j.1365-2265.2002.01643.x

Cited by 77 publications

(49 citation statements)

References 27 publications

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“…Subsequently, the same genetic defects have been detected in some sporadic endocrine tumors, such as adrenal and thyroid adenomas and carcinomas (16 -18). Conversely, a role of PKA R1A in the pathogenesis of pituitary tumors has been ruled out based on the absence of both gene mutations and loss of heterozygosity reported by previous studies and confirmed in the present series (15,19,20).…”

Section: Discussionsupporting

confidence: 62%

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

et al. 2004

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The two regulatory subunits (R1 and R2) of protein kinase A (PKA) are differentially expressed in cancer cell lines and exert diverse roles in growth control. Recently, mutations of the PKA regulatory subunit 1A gene (PRKAR1A) have been identified in patients with Carney complex. The aim of this study was to evaluate the expression of the PKA regulatory subunits R1A, R2A, and R2B in a series of 30 pituitary adenomas and the effects of subunit activation on cell proliferation. In these tumors, neither mutation of PRKAR1A nor loss of heterozygosity was identified. By realtime PCR, mRNA of the three subunits was detected in all of the tumors, R1A being the most represented in the majority of samples. By contrast, immunohistochemistry documented low or absent R1A levels in all tumors, whereas R2A and R2B were highly expressed, thus resulting in an unbalanced R1/R2 ratio. The low levels of R1A were, at least in part, due to proteasome-mediated degradation. The effect of the R1/R2 ratio on proliferation was assessed in GH3 cells, which showed a similar unbalanced pattern of R subunits expression, and in growth hormone-secreting adenomas. The R2-selective cAMP analog 8-Cl cAMP and R1A RNA silencing, stimulated cell proliferation and increased Cyclin D1 expression, respectively, in human and rat adenomatous somatotrophs. These data show that a low R1/R2 ratio promoted proliferation of transformed somatotrophs and are consistent with the Carney complex model in which R1A inactivating mutations further unbalance this ratio in favor of R2 subunits. These results suggest that low expression of R1A protein may favor cAMP-dependent proliferation of transformed somatotrophs.

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Section: Discussionsupporting

confidence: 62%

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

et al. 2004

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“…In each of these cases, the establishment of autonomous hyperproliferative cells may be due to the immortalizing effect of increased PKA signaling, although, as above, there is little impetus toward malignant transformation in the absence of additional mutations. In fact, down-regulation of PRKAR1A has recently been described in sporadic growth hormone-producing adenomas (32), although mutations in PRKAR1A are rarely, if ever, observed in these tumors (33,34).…”

Section: Cancer Researchmentioning

confidence: 99%

Disruption of Protein Kinase A Regulation Causes Immortalization and Dysregulation of D-Type Cyclins

Nadella

Kirschner

2005

Cancer Research

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Phosphorylation is a key event in cell cycle control, and dysregulation of this process is observed in many tumors, including those associated with specific inherited neoplasia syndromes. We have shown previously that patients with the autosomal dominant tumor predisposition Carney complex carry inactivating mutations in the PRKAR1A gene, which encodes the type 1A regulatory subunit of protein kinase A (PKA), the cyclic AMP-dependent protein kinase. This defect was associated with dysregulation of PKA signaling, and genetic analysis has suggested that complete loss of the gene may be required for tumorigenesis. To determine the mechanism by which dysregulation of PKA causes tumor formation, we generated in vitro primary mouse cells lacking the Prkar1a protein. We report that this genetic disruption of PKA regulation causes constitutive PKA activation and immortalization of primary mouse embryonic fibroblasts (MEFs). At the molecular level, knockout of Prkar1a leads to up-regulation of D-type cyclins, and this increase occurs independently of other pathways known to increase cyclin D levels. Despite the immortalized phenotype, known mediators of cellular senescence (e.g., p53 and p19 ARF ) seem to remain intact in Prkar1a À/À MEFs. Mechanistically, cyclin D1 mRNA levels are not altered in the knockout cells, but protein half-life is markedly increased. Using this model, we provide the first direct genetic evidence that dysregulation of PKA promotes important steps in tumorigenesis, and that cyclin D1 is an essential target of PKA. (Cancer Res 2005; 65(22): 10307-15)

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“…Although the evidence suggests that this may be the case in CNC, it is not known whether PRKAR1A can cause sporadic pituitary tumors when mutated at the somatic level. Three recent studies [42][43][44] have demonstrated that PRKAR1A is an unlikely molecular etiology of non-familial pituitary tumors, not unlike the case of menin, the MEN 1 gene [45].…”

Section: Is Prkar1a Mutated In Other Pituitary Tumors?mentioning

confidence: 99%

Pituitary Pathology in Carney Complex Patients

et al. 2004

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Carney complex (CNC) is a familial multiple neoplasia syndrome with features overlapping those of McCune-Albright syndrome (MAS) and multiple endocrine neoplasia (MEN) type 1 (MEN 1). Like MAS and MEN 1 patients, patients with CNC develop growth hormone (GH)-producing pituitary tumors. Occasionally, these tumors are also prolactin-producing, but there are no isolated pro-lactinomas or other types of pituitary tumors. In at least some patients with CNC, the pituitary gland is characterized by hyperplastic areas; hyperplasia appears to involve somatomammotrophs only. Hyperplasia most likely precedes the formation of GH-producing adenomas in CNC, as has been suggested in MAS-related somatotropinomas, but has never been seen in MEN 1 patients. In at least one case of a patient with CNC and advanced acromegaly, a GH-producing macroadenoma showed extensive genetic changes at the chromosomal level. So far, 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-hererozygosity suggests that PRKAR1A, which codes for the regulatory subunit type 1α of the cAMP-dependent protein kinase A (PKA) may act as a tumor-suppressor gene in CNC somatomammotrophs. These data provide evidence for a PRKAR1A-induced somatomammotroph hyperpasia in the pituitary tissue of CNC patients; hyperplasia, in turn may lead to additional genetic changes at the somatic level, which then cause the formation of adenomas in some, but not all, patients.

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Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours

Abstract: No mutations were found in any of the exons sequenced. Relative mRNA expression was not decreased in any of the sporadic pituitary tumour samples. The present data thus do not suggest a major role for the PRKAR1A tumour suppressor gene in sporadic GH-secreting or other pituitary tumours.

Cited by 77 publications

References 27 publications

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

Disruption of Protein Kinase A Regulation Causes Immortalization and Dysregulation of D-Type Cyclins

Pituitary Pathology in Carney Complex Patients

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