Protein-Kinase A and Human Disease: The Core of cAMP-Dependent Signaling in Health and Disease

Introduction

Ever since the discovery of the cyclic AMP (cAMP)-dependent signaling pathway in the mid-1960s, there has been considerable debate about its involvement in the control of cellular growth and proliferation. Does cAMP stimulate, or does it inhibit growth [1] [2] [3]? What are the conditions under which there is negative regulation, and what are the circumstances that favor induction of growth and proliferation? Surprisingly, despite the advances of molecular genetics, the answers to these questions, which were first raised several years ago, remain elusive.

For the last 15 years, the cAMP pathway has been found to be responsible for a series of diseases that predispose to tumor development, albeit mostly benign. The most recent among these discoveries is the identification of PRKAR1A, the gene that codes for the relatively abundant regulatory subunit type 1A of protein kinase A, as the tumor suppressor gene responsible for the multiple endocrine neoplasia syndrome known as “Carney complex” (the syndrome of spotty skin pigmentation, myxomas and endocrine overactivity) [4] [5] [6]. The text that follows is a compilation of presentations that were given during an international meeting held recently at the National Institutes of Health and sponsored by the National Institutes of Child Health and Human Development. Although the meeting did not give answers to the age-old questions mentioned above, it provided the most recent update on this issue and will hopefully contribute to an impetus for more research on the subject.

References

• 1 Gottesman M M, Fleischmann R D. The role of cAMP in regulating tumour cell growth.  Cancer Surv. 1986;  5 291-308
• 2 Dumont J E, Jauniaux J C, Roger P P. The cyclic AMP-mediated stimulation of cell proliferation.  Trends Biochem Sci. 1989;  14 67-71
• 3 Thorner J. An essential role for cyclic AMP in growth control: the case for yeast.  Cell. 1982;  30 5-6
• 4 Stratakis C A, Kirschner L S, Carney J A. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.  J Clin Endocrinol Metab. 2001;  86 4041-4046
• 5 Kirschner L S, Sandrini F, Monbo J, Lin J P, Carney J A, Stratakis C A. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex.  Hum Mol Genet. 2000;  9 3037-3046
• 6 Kirschner L S, Carney J A, Pack S D, Taymans S E, Giatzakis C, Cho Y S, Cho-Chung Y S, Stratakis C A. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.  Nat Genet. 2000;  26 89-92