Poster abstracts

Poster number 78 submitted by Emilia Pavel Mahoney

Alterations in Wnt Signaling in Bone Neoplasia Driven by PKA Dysregulation

Emilia Pavel Mahoney (MVIMG- OSU), Kiran Nadella (MVIMG - OSU), Alyssa Charrier (MCDB - OSU), Lawrence S. Kirschner (MVIMG, Internal Medicine, Division of Endocrinology, OSU)

Abstract:
Carney Complex is an autosomal dominant neoplasia syndrome caused by inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of protein kinase A (PKA) (1). This genetic defect induces skin pigmentation, endocrine tumors, myxomas, schwannomas and bone tumors-osteochondromyxomas (2).
We have a Prkar1a +/- mouse model (3) that develops boney tumors in which gene and protein expression analysis revealed alterations in the Wnt signaling pathway (4). This pathway is known to be involved in skeletogenesis and tumorigenesis. Upon investigating the Wnt pathway in these bone tumors, we found an increase in the amount and activity of beta-catenin in the nucleus of tumor osteoblasts. Further analysis revealed a peculiar speckled pattern of beta-catenin in the nucleus of the tumor cells that co-localizes with PML protein; a pattern not seen in the wild-type osteoblasts unless treated with Forskolin (PKA stimulatory agent).
PKA phosphorylates beta-catenin at two sites, unrelated to GSK3 ubiquitination (5), however the consequences of this interaction are not known. We introduced a mutation at the PKA phospho-site in beta-catenin and the results of our investigation suggest that the increase in PKA activity may trigger a change in cellular distribution of beta-catenin and formation of a complex with PML protein. The cooperation between these molecules may function to influence the transcription of the genes found to be altered in these bone tumors. We are currently analyzing the promoter region of these genes to find which ones are the targets of this complex and what cellular functions are ultimately altered.
This study brings new insights about two important pathways – PKA and Wnt – and investigates how the consequences of their interaction lead to tumor formation.

References:
1. Kirschner, L.S., et al.,Nat Genet, 2000. 26(1): p. 89-92
2. Carney JA, et al., Am J Surg Pathol 2001 25:164–176
3. Kirschner, L.S., et al., Cancer Res, 2005. 65(11): p. 4506-14
4. Pavel, E., et al., Mol Endocrinol, 2008. 22(2): p. 430-40
5. Taurin, S., et al., J Biol Chem, 2006. 281(15): p. 9971-6

Keywords: tumor, osteoblast, Wnt