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Gene Review

Prkar1a  -  protein kinase, cAMP dependent regulatory,...

Mus musculus

Synonyms: 1300018C22Rik, RIalpha, Tse-1, Tse1, cAMP-dependent protein kinase type I-alpha regulatory subunit
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Disease relevance of Prkar1a

  • Prkar1a(+/-) mice developed nonpigmented schwannomas and fibro-osseous bone lesions beginning at approximately 6 months of age [1].
  • To assess the activity of Tse-1 in other tissues, we transferred mouse chromosome 11 from several different cell types into rat hepatoma recipients [2].
  • Effects of RIalpha overexpression on cisplatin sensitivity in human ovarian carcinoma cells [3].
  • Intraperitoneal administration of this antisense RIalpha poly-DNP-RNA to SCID mice with transplanted MDA-MB-231 cells was found to inhibit the growth of the xenografts in a concentration-dependent way, prevent metastasis, and drastically reduce mortality [4].
  • Prostaglandin E2 (PGE2) stimulated in vitro invasion, migration, and adherence to reconstituted basement membrane by metastatic Lewis lung carcinoma (LLC) clones, but this stimulation was blocked by protein kinase A (PKA) inhibitors and by expression of a transfected mutant RI alpha which blocks PKA activation [5].
  • Although prolactinomas were observed in KO and control mice, the KO mice exhibited a significantly increased frequency of pituitary tumors compared with wild-type or conventional Prkar1a(+/-) mice [6].

High impact information on Prkar1a


Chemical compound and disease context of Prkar1a


Biological context of Prkar1a


Anatomical context of Prkar1a


Associations of Prkar1a with chemical compounds

  • This mouse provides a novel, useful tool for the investigation of cyclic AMP, RIalpha, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues [13].
  • Holoenzymes containing RI beta Ala and RI beta Ala/Ile gave Ka values which were higher than wild type RI beta, with the double mutant shifting toward the Ka value of RI alpha holoenzymes by about 30% [18].
  • The 18-mer antisense DNA against the RIalpha subunit of PKA was conjugated via a primary amine on the 5'-end with the NHS esters of HYNIC and MAG3 and by the cyclic anhydride of DTPA [19].
  • Retroviral-infected A2780 cells overexpressing wild-type RI alpha cDNA displayed a four- to eightfold greater sensitivity to cisplatin compared with parental cells [3].
  • The nucleotide sequence indicated that the transforming activity was created by the fusion of the ret tyrosine kinase domain with part of the RI alpha regulatory subunit of protein kinase A (PKA) [20].

Regulatory relationships of Prkar1a

  • The capacity of PKA to regulate the cytoskeletal organization of tumor cells was further studied with the use of LLC variants that had been stably transfected to over-express the C alpha subunit of PKA (CEV cells) or to express a mutant cAMP-resistant PKA RI alpha subunit resulting in a defective PKA (REV cells) [21].
  • In addition to having catalytic activity, the C alpha subunit from Kin- cells is inhibited in the presence of mouse RI alpha regulatory subunit, indicating that formation of the holoenzyme complex is normal [22].
  • These results suggest a novel mechanism of cAMP signaling through the interaction of RIalpha with CoxVb thereby regulating cytochrome c oxidase activity as well as the cytochrome c levels [23].

Other interactions of Prkar1a

  • In addition, RI alpha recruits C alpha protein to the junction, providing at this site the potential for local responsiveness to cAMP [14].
  • This assignment demonstrated that the Tat-1 structural gene was not syntenic with Tse-1, a chromosome 11-linked locus that negatively regulates TAT expression in trans (A. M. Killary and R. E. K. Fournier, Cell 38:523-534, 1984) [24].
  • This is apparently the first report of an RIalpha-specific protein kinase A anchoring protein tethering domain [15].
  • Brachyury mRNA expression in the primitive streak of RIalpha mutants is significantly reduced, consistent with later deficits in axial, paraxial, and lateral plate mesodermal derivatives [16].
  • We have created null mutations in the RIbeta and RIIbeta regulatory subunit genes in mice, and find that both result in an increase in the level of RIalpha protein in tissues that normally express the beta isoforms [17].

Analytical, diagnostic and therapeutic context of Prkar1a


  1. A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Kirschner, L.S., Kusewitt, D.F., Matyakhina, L., Towns, W.H., Carney, J.A., Westphal, H., Stratakis, C.A. Cancer Res. (2005) [Pubmed]
  2. Differential activity of a tissue-specific extinguisher locus in hepatic and nonhepatic cells. Gourdeau, H., Peterson, T.C., Fournier, R.E. Mol. Cell. Biol. (1989) [Pubmed]
  3. Effects of RIalpha overexpression on cisplatin sensitivity in human ovarian carcinoma cells. Cvijic, M.E., Chin, K.V. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  4. Growth inhibition and antimetastatic effect of antisense poly-DNP-RNA on human breast cancer cells. Ru, K., Schmitt, S., James, W.I., Wang, J.H. Oncol. Res. (1999) [Pubmed]
  5. Activation of protein kinase A increases the in vitro invasion, migration, and adherence to reconstituted basement membrane by Lewis lung carcinoma tumor cells. Young, M.R., Young, M.E., Lozano, Y., Bagash, J.M. Invasion Metastasis (1992) [Pubmed]
  6. Pituitary-specific knockout of the Carney complex gene Prkar1a leads to pituitary tumorigenesis. Yin, Z., Williams-Simons, L., Parlow, A.F., Asa, S., Kirschner, L.S. Mol. Endocrinol. (2008) [Pubmed]
  7. Two genetically defined trans-acting loci coordinately regulate overlapping sets of liver-specific genes. Ruppert, S., Boshart, M., Bosch, F.X., Schmid, W., Fournier, R.E., Schütz, G. Cell (1990) [Pubmed]
  8. A genetic analysis of extinction: trans-dominant loci regulate expression of liver-specific traits in hepatoma hybrid cells. Killary, A.M., Fournier, R.E. Cell (1984) [Pubmed]
  9. Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Cummings, D.E., Brandon, E.P., Planas, J.V., Motamed, K., Idzerda, R.L., McKnight, G.S. Nature (1996) [Pubmed]
  10. A single-injection protein kinase A-directed antisense treatment to inhibit tumour growth. Nesterova, M., Cho-Chung, Y.S. Nat. Med. (1995) [Pubmed]
  11. Protein kinase A RIalpha antisense inhibition of PC3M prostate cancer cell growth: Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation. Cho, Y.S., Kim, M.K., Tan, L., Srivastava, R., Agrawal, S., Cho-Chung, Y.S. Clin. Cancer Res. (2002) [Pubmed]
  12. Dermal mast cell activation by autoantibodies against the high affinity IgE receptor in chronic urticaria. Niimi, N., Francis, D.M., Kermani, F., O'Donnell, B.F., Hide, M., Kobza-Black, A., Winkelmann, R.K., Greaves, M.W., Barr, R.M. J. Invest. Dermatol. (1996) [Pubmed]
  13. Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors. Griffin, K.J., Kirschner, L.S., Matyakhina, L., Stergiopoulos, S., Robinson-White, A., Lenherr, S., Weinberg, F.D., Claflin, E., Meoli, E., Cho-Chung, Y.S., Stratakis, C.A. Cancer Res. (2004) [Pubmed]
  14. Accumulation in fetal muscle and localization to the neuromuscular junction of cAMP-dependent protein kinase A regulatory and catalytic subunits RI alpha and C alpha. Imaizumi-Scherrer, T., Faust, D.M., Bénichou, J.C., Hellio, R., Weiss, M.C. J. Cell Biol. (1996) [Pubmed]
  15. Identification of tethering domains for protein kinase A type Ialpha regulatory subunits on sperm fibrous sheath protein FSC1. Miki, K., Eddy, E.M. J. Biol. Chem. (1998) [Pubmed]
  16. Increased basal cAMP-dependent protein kinase activity inhibits the formation of mesoderm-derived structures in the developing mouse embryo. Amieux, P.S., Howe, D.G., Knickerbocker, H., Lee, D.C., Su, T., Laszlo, G.S., Idzerda, R.L., McKnight, G.S. J. Biol. Chem. (2002) [Pubmed]
  17. Compensatory regulation of RIalpha protein levels in protein kinase A mutant mice. Amieux, P.S., Cummings, D.E., Motamed, K., Brandon, E.P., Wailes, L.A., Le, K., Idzerda, R.L., McKnight, G.S. J. Biol. Chem. (1997) [Pubmed]
  18. Holoenzymes of cAMP-dependent protein kinase containing the neural form of type I regulatory subunit have an increased sensitivity to cyclic nucleotides. Cadd, G.G., Uhler, M.D., McKnight, G.S. J. Biol. Chem. (1990) [Pubmed]
  19. Influence of different chelators (HYNIC, MAG3 and DTPA) on tumor cell accumulation and mouse biodistribution of technetium-99m labeled to antisense DNA. Zhang, Y.M., Liu, N., Zhu, Z.H., Rusckowski, M., Hnatowich, D.J. European journal of nuclear medicine. (2000) [Pubmed]
  20. Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A. Bongarzone, I., Monzini, N., Borrello, M.G., Carcano, C., Ferraresi, G., Arighi, E., Mondellini, P., Della Porta, G., Pierotti, M.A. Mol. Cell. Biol. (1993) [Pubmed]
  21. Activation of the protein kinase a signal transduction pathway by granulocyte-macrophage colony-stimulating factor or by genetic manipulation reduces cytoskeletal organization in Lewis lung carcinoma variants. Young, M.R., Charboneau, S., Lozano, Y., Djordjevic, A., Young, M.E. Int. J. Cancer (1994) [Pubmed]
  22. The S49 Kin- cell line transcribes and translates a functional mRNA coding for the catalytic subunit of cAMP-dependent protein kinase. Orellana, S.A., McKnight, G.S. J. Biol. Chem. (1990) [Pubmed]
  23. Novel function of the regulatory subunit of protein kinase A: regulation of cytochrome c oxidase activity and cytochrome c release. Yang, W.L., Iacono, L., Tang, W.M., Chin, K.V. Biochemistry (1998) [Pubmed]
  24. Chromosomal assignment and trans regulation of the tyrosine aminotransferase structural gene in hepatoma hybrid cells. Peterson, T.C., Killary, A.M., Fournier, R.E. Mol. Cell. Biol. (1985) [Pubmed]
  25. 8-Chloroadenosine mediates 8-chloro-cyclic AMP-induced down-regulation of cyclic AMP-dependent protein kinase in normal and neoplastic mouse lung epithelial cells by a cyclic AMP-independent mechanism. Lange-Carter, C.A., Vuillequez, J.J., Malkinson, A.M. Cancer Res. (1993) [Pubmed]
  26. Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RIalpha subunit of protein kinase A after oral administration. Wang, H., Cai, Q., Zeng, X., Yu, D., Agrawal, S., Zhang, R. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
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