Gene Expression Signatures of cAMP/Protein Kinase A (PKA)-promoted, Mitochondrial-dependent Apoptosis

Abstract

The ability of the second messenger cAMP to alter the balance between cell growth and apoptosis is cell type-dependent. cAMP stimulates growth and inhibits apoptosis in some cell types, such as neuronal cells (1), but it promotes growth arrest and apoptosis in other types of cells, such as poorly differentiated lymphoid cells (2). In addition, cAMP analogs can enhance the pro-apoptotic effects of glucocorticoids, for example, of glucocorticoid-resistant multiple myeloma and leukemia cells (2-5). However, the mechanisms that mediate cAMP-induced apoptosis are poorly understood.Cyclic AMP-promoted apoptosis of lymphoid, in particular T-cell-derived lymphoma, cells depends on the principal effector of cAMP action, protein kinase A (PKA) 3 (2-4, 6). Although both PKA and the exchange protein directly activated by cyclic AMP (Epac), another mediator of cAMP action, are found in lymphoid cells, Epac does not appear to be involved in cAMPmediated control of the cell cycle (7) or apoptosis in these cells (2,8). Overexpression of certain anti-apoptotic proteins, such as Bcl-2, can protect lymphoma cells from cAMP-mediated apoptosis; such protection appears to be distinct from effects of cAMP on cell cycle arrest (9). Thus, cAMP-promoted growth arrest and apoptosis appear to occur via distinct mechanisms.S49 lymphoma cells are a unique model system to explore cell growth arrest and apoptosis by the cAMP/PKA pathway. S49 cells, which arose in a BALB/c mouse as a T-cell tumor, grow in suspension culture with a doubling time of 14 -16 h and undergo G 1 growth arrest and apoptosis in response to elevation of cAMP (10, 11). S49 clonal variants have been isolated that are resistant to killing by cAMP or agents that increase cAMP levels. One of these cAMP-resistant variants, D Ϫ (cAMP deathless) S49 cells, has normal PKA activity and cAMP-promoted growth arrest in G 1 but lacks cAMP-promoted apoptosis (12). * This work was supported by Grants from the Leukemia and Lymphoma Society, National Institutes of Health (GM61774), and National Institutes of Health sponsored Institutional Research and Academic Career Development Award (IRACDA) fellowship (GM06852). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Cotranslational cis -phosphorylation of the COOH-terminal tail is a key priming step in the maturation of cAMP-dependent protein kinase

“…Mg 2 ATP is required for formation of the RI α holoenzyme; therefore, the C-subunit assumes a fully closed conformation, but the phosphate on Ser 338 has no direct contact with the R-subunit (5). suspension culture and undergo mitochondria-dependent apoptosis in response to increases in intracellular cAMP (31). Kin− S49 cells, which were selected based on their resistance to cAMP-promoted apoptosis, have no detectable C-subunit or PKA activity in the soluble fractions, except a small amount of C-subunit in the insoluble fraction (32,33).…”

A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells

“…Rev-2-T6 (PKA + ) and KinA À cells were derived from the S49 BALB/c T-cell lymphoma, a unique model system for exploring various parameters affected by the cAMP/PKA pathway (36,38,54,55). The KinA À cells are commonly used as a PKA-deficient cell line (55)(56)(57).…”

A Role for cAMP and Protein Kinase A in Experimental Necrotizing Enterocolitis

“…Evidence supports that PKA is proapoptotic through the phosphorylation of protein targets, and studies in lymphoma cells have demonstrated that apoptosis results via an intrinsic mitochondrialdependent mechanism. 40,68 In addition, cAMP and PKA are known to effect immune cell function, and elevations in cAMP have been associated with inhibition of T lymphocyte activity 69 and IL production. 70 Thus, the in vivo role of PKA inhibition may have multiple downstream effects that function in concert to protect against experimental NEC in our models.…”