PRKAR1A and the evolution of pituitary tumors

Abstract

Carney complex (CNC) is an inherited tumor predisposition associated with pituitary tumors, including GH-producing pituitary adenomas and rare reports of prolactinomas. This disease is caused by mutations in PRKAR1A, which encodes the type 1A regulatory subunit of the cAMP-dependent protein kinase, PKA. Loss of PRKAR1A causes enhanced PKA signaling, which leads to pituitary tumorigenesis. Mutations in the gene have not been detected in sporadic pituitary tumors, but there is some data to suggest that non-genomic mechanisms may cause loss of protein expression. Unlike CNC patients, mice heterozygous for Prkar1a mutations do not develop pituitary tumors, although complete knockout of the gene in the Pit1 lineage of the pituitary produces GH-secreting pituitary adenomas. These data indicate that complete loss of Prkar1a/PRKAR1A is able to cause pituitary tumors in mice and men. The pattern of tumors is likely related to the signaling pathways employed in specific pituitary cell types.

Figure 1

Histopathology of pituitary tumors from Prkar1a-PitKO mice. A. Hematoxylin and eosin staining of a pituitary showing the presence of 2 microadenoms (white arrows). B. Mitotic figures (yellow arrows) observed within a different pituitary tumor. Scale bars are indicated for each panel.

Figure 2

Model for the connection between PRKAR1A mutations and acromegaly. A. The primary signaling pathways connecting hypothalamic signaling to pituitary hormone secretion are indicated for each cell type of the Pit1 lineage. See text for references. Note that Somatotrophs are primarily dependent on cAMP/PKA signaling for this process. B. Loss of PRKAR1A or activation of Gsα can cause secretion of GH independent of upstream signals.