Down-Regulation of Regulatory Subunit Type 1A of Protein Kinase A Leads to Endocrine and Other Tumors

Griffin, Kurt J.; Kirschner, Lawrence S.; Matyakhina, Ludmila; Stergiopoulos, Sotirios; Robinson‐White, Audrey; Lenherr, Sara; Weinberg, Frank; Claflin, E. S.; Meoli, Elise; Cho‐Chung, Yoon S.; Stratakis, Constantine A.

doi:10.1158/0008-5472.can-04-3620

Cited by 94 publications

(78 citation statements)

References 18 publications

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“…Down-regulation of Prkar1a was shown in vitro and in vivo at both mRNA and protein levels (28), and the mice were observed to develop thyroid hyperplasia similar to that observed in human patients (29). These mice were also prone to the development of lymphomas and sarcomas, although these tumors are not frequent in Carney complex patients, and their significance is unknown.…”

Section: Discussionmentioning

confidence: 84%

A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP–Responsive Tissues

et al. 2005

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Carney complex is an autosomal dominant neoplasia syndrome characterized by spotty skin pigmentation, myxomatosis, endocrine tumors, and schwannomas. This condition may be caused by inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of protein kinase A. To better understand the mechanism by which PRKAR1A mutations cause disease, we have developed conventional and conditional null alleles for Prkar1a in the mouse. Prkar1a +/À mice developed nonpigmented schwannomas and fibro-osseous bone lesions beginning at f6 months of age. Although genotype-specific cardiac and adrenal lesions were not seen, benign and malignant thyroid neoplasias were observed in older mice. This spectrum of tumors overlaps that seen in Carney complex patients, confirming the validity of this mouse model. Genetic analysis indicated that allelic loss occurred in a subset of tumor cells, suggesting that complete loss of Prkar1a plays a key role in tumorigenesis. Similarly, tissue-specific ablation of Prkar1a from a subset of facial neural crest cells caused the formation of schwannomas with divergent differentiation. These observations confirm the identity of PRKAR1A as a tumor suppressor gene with specific importance to cyclic AMP-responsive tissues and suggest that these mice may be valuable tools not only for understanding endocrine tumorigenesis but also for understanding inherited predispositions for schwannoma formation. (Cancer Res 2005; 65(11): 4506-14)

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Section: Discussionmentioning

confidence: 84%

A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP–Responsive Tissues

et al. 2005

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“…Although PKARI␣ may act as a "tumor suppressor" in CNC, previous studies have also reported that PKARI␣ facilitates the cell proliferative signaling of hormones and growth factors in certain types of cancer cells (46) and depletion of PKARI␣ effectively inhibits transcription of certain genes and growth of tumor cells (47). Thus, PKARI␣ may augment or inhibit cellular proliferation in a cell type-specific manner.…”

Section: Pp2a Exists In a Complex With Rsk1⅐pka⅐d-akap1 And Ht31mentioning

confidence: 99%

The PKARIα Subunit of Protein Kinase A Modulates the Activation of p90RSK1 and Its Function

Chaturvedi

Cohen

Taunton

et al. 2009

Journal of Biological Chemistry

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Cyclic AMP-dependent protein kinase (PKA) 3 plays a pivotal role in manifesting an array of biological actions ranging from cell proliferation and tumorigenesis to increased inotropic and chronotropic effects in the heart as well as regulation of long term potentiation and memory. The PKA holoenzyme is a heterotetramer and consists of two catalytic (PKAc) subunits bound to a dimer of regulatory subunits. To date, four isoforms of the PKAc (PKAc␣, PKAc␤, PKAc␥, and PKAc␦) and four isoforms of the regulatory subunits (RI␣, RI␤, RII␣, and RII␤) have been described (1). The various isoforms of PKA subunits are expressed differently in a tissue-and cell-specific manner (2). In addition to binding and inhibiting the activity of PKAc via their pseudo substrate region (3-6), the R subunits also interact with PKA-anchoring proteins (AKAPs) and facilitate the localization of PKA in specific subcellular compartments (7,8). More than 50 AKAP family members have been described, and although most of these have a higher affinity for the RII subunits (9), certain AKAPs such as D-AKAP1 and D-AKAP2 preferentially bind the PKARI␣ subunit (10 -12). Because the AKAPs also bind other signaling molecules such as phosphatases (PP2B) and kinases (protein kinase C), they act as scaffolds to organize and integrate specific signaling events within specific compartments in the cells (7,8,13,14).We have shown that the PKARI␣ and PKAc␣ subunits of PKA interact with the inactive and active forms of p90 RSK1 (RSK1), respectively (15). Binding of inactive RSK1 to PKARI␣ decreases the interactions between PKARI␣ and PKAc, whereas the association of active RSK1 with PKAc increases interactions between PKARI␣ and PKAc such that larger amounts of cAMP are required to activate PKAc in the presence of active RSK1 (15). Moreover, the indirect (via subunits of PKA) interaction of RSK1 with AKAPs is required for the nuclear localization of active RSK1 (15), and disruption of the interactions of RSK1⅐PKA complex from AKAPs results in increased cytoplasmic distribution of active RSK1 with a concomitant increase in phosphorylation of its cytosolic substrates such as BAD and reduced cellular apoptosis (15). These findings show the functional and biological significance of RSK1⅐ PKA⅐AKAP interactions.Besides inhibiting PKAc activity, the physiological role of PKARI␣ is underscored by the findings that mutations in the PKAR1A gene that result in haploinsufficiency of PKARI␣ are

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“…Perhaps, the best example of a RET fusion partner, whose altered function may contribute to neoplastic transformation is the regulatory subunit type I-a of protein kinase A (PRKAR1A) that is involved in RET/ PTC2. PRKAR1A is, indeed, a bona fide tumor suppressor (65) and its ablation in the mouse induced the formation of thyroid tumors (66). The knowledge about the function of the other RET fusion partners is limited.…”

Section: Molecular Mechanisms Of Activation Of Ret/ptc Oncoproteinsmentioning

confidence: 99%

RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture

Santoro¹,

Melillo²,

Fusco³

2006

eur j endocrinol

178

118

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Papillary thyroid carcinoma (PTC) is frequently associated with RET gene rearrangements that generate the so-called RET/PTC oncogenes. In this review, we examine the data about the mechanisms of thyroid cell transformation, activation of downstream signal transduction pathways and modulation of gene expression induced by RET/PTC. These findings have advanced our understanding of the processes underlying PTC formation and provide the basis for novel therapeutic approaches to this disease.European Journal of Endocrinology 155 645-653

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Down-Regulation of Regulatory Subunit Type 1A of Protein Kinase A Leads to Endocrine and Other Tumors

Cited by 94 publications

References 18 publications

A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP–Responsive Tissues

A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP–Responsive Tissues

The PKARIα Subunit of Protein Kinase A Modulates the Activation of p90RSK1 and Its Function

RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture

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