Protein Kinase A Alterations in Endocrine Tumors

B. Yu; B. Ragazzon; M. Rizk-Rabin; J. Bertherat

doi:10.1055/s-0032-1316292

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2012; 44(10): 741-748
DOI: 10.1055/s-0032-1316292

Review

Protein Kinase A Alterations in Endocrine Tumors

B. Yu

¹Institut Cochin, INSERM U1016, Paris, France

²CNRS UMR8104, Paris, France

³Sorbonne Paris Cité, Université Paris Descartes, Paris, France

,

B. Ragazzon

¹Institut Cochin, INSERM U1016, Paris, France

²CNRS UMR8104, Paris, France

³Sorbonne Paris Cité, Université Paris Descartes, Paris, France

,

M. Rizk-Rabin

¹Institut Cochin, INSERM U1016, Paris, France

²CNRS UMR8104, Paris, France

³Sorbonne Paris Cité, Université Paris Descartes, Paris, France

,

J. Bertherat

¹Institut Cochin, INSERM U1016, Paris, France

²CNRS UMR8104, Paris, France

³Sorbonne Paris Cité, Université Paris Descartes, Paris, France

⁴Assistance Publique Hôpitaux de Paris, Center for Rare Adrenal Diseases, Hôpital Cochin, Paris, France

› Institutsangaben

Abstract

Various molecular and cellular alterations of the cyclic adenosine monophosphate (cAMP) pathway have been observed in endocrine tumors. Since protein kinase A (PKA) is a central key component of the cAMP pathway, studies of the alterations of PKA subunits in endocrine tumors reveal new aspects of the mechanisms of cAMP pathway alterations in human diseases. So far, most alterations have been observed for the regulatory subunits, mainly PRKAR1A and to a lower extent, PRKAR2B. One of the best examples of such alteration today is the multiple neoplasia syndrome Carney complex (CNC). The most common endocrine gland manifestations of CNC are pituitary GH-secreting adenomas, thyroid tumors, testicular tumors, and ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). Heterozygous germline inactivating mutations of the PKA regulatory subunit RIα gene (PRKAR1A) are observed in about two-third of CNC patients, and also in patients with isolated PPNAD. PRKAR1A is considered as a tumor suppressor gene. Interestingly, these mutations can also be observed as somatic alterations in sporadic endocrine tumors. More than 120 different PRKAR1A mutations have been found today. Most of them lead to an unstable mutant mRNA, which will be degraded by nonsense mediated mRNA decay. In vitro and in vivo functional studies are in progress to understand the mechanisms of endocrine tumor development due to PKA regulatory subunits inactivation. PRKAR1A mutations stimulate in most models PKA activity, mimicking in some way cAMP pathway constitutive activation. Cross-talks with other signaling pathways summarized in this review have been described and might participate in endocrine tumorigenesis.

Key words

cAMP - PKA - adrenal tumors - pituitary tumors

Volltext

Referenzen

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