Platelet-Derived Growth Factor BB Induces Nuclear Export and Proteasomal Degradation of CREB via Phosphatidylinositol 3-Kinase/Akt Signaling in Pulmonary Artery Smooth Muscle Cells

Abstract

. These results indicate that in addition to direct phosphorylation, proteolysis and intracellular localization are key mechanisms regulating CREB content and activity in SMCs.Pulmonary hypertension (PH) and related vascular pathologies are characterized by changes in the structure of the arterial wall. These changes are largely due to the proliferation and hypertrophy of smooth muscle cells (SMCs) and increased SMC deposition of extracellular matrix in the vessel wall. The proliferation and hypertrophy of SMCs are stimulated by growth factors and proinflammatory agents such as plateletderived growth factor BB (PDGF-BB), insulin-like growth factors I and II, epidermal growth factor, basic fibroblast growth factor, vascular endothelial growth factor, endothelin-1, and thrombospondin-1, which are produced by endothelial cells, SMCs, fibroblasts, and platelets in response to vascular injury (6,11,14,15,46,59). Binding of these growth factors to their respective receptors activates associated tyrosine kinases, G proteins, and C-type phospholipases. Activation of receptor tyrosine kinases stimulates mitogen-activated protein kinase (MAPK) signaling cascades, with PDGF-BB stimulation of extracellular signal-regulated kinase 1 (ERK1)/ERK2 being a widely studied example (23, 44). G protein-coupled receptors may regulate numerous signaling pathways, with recent studies implicating RhoA/Rho kinase signaling in SMC growth and migration (52). These signaling pathways modulate the activity of downstream effectors of growth such as cyclin-dependent kinases (42) and immediate-early genes (49).These growth-promoting pathways are normally restrained in healthy arteries by endogenous mediators such as prostacyclin and NO. These agents exert antiproliferative effects on SMCs largely by increasing intracellular levels of cyclic nucleotides (53, 54), which stimulate the activity of protein kinase A (PKA) and GMP-stimulated protein kinase. Many compounds that activate adenyl cyclase (39), inhibit phosphodiesterases (50), or mimic cyclic AMP (cAMP)/cGMP (34) exert antiproliferative effects on SMC growth. Interestingly, many drugs and therapeutic agents that reduce SMC proliferation act by increasing intracellular cAMP levels (22,27,44,64). There is now substantial evidence that cAMP/PKA signaling acts as a molecular gate to block MAPK-induced proliferation in response to mitogens such as PDGF (5,23,30,44). Activation of cAMP signaling in SMCs decreases the expression of cyclin D1 and Cdk2 (60), increases the expression of antiproliferative molecules such as p53 and p21 (25), and increases overall sensitivity to antiproliferative stimuli.Given the potent proliferation-suppressing action of cAMP on SMCs, we hypothesized that the transcription factor CREB,

Coregulated Ataxia Telangiectasia-mutated and Casein Kinase Sites Modulate cAMP-response Element-binding Protein-Coactivator Interactions in Response to DNA Damage

“…The phosphorylation of CREB on Ser-121 was reported to target CREB for proteasome-dependent degradation in response to prolonged hypoxia (44). The same site was implicated in CREB degradation in cardiac smooth muscle cells following platelet-derived growth factor treatment (45). However, IR doses up to 30 Gy do not cause changes in steady-state CREB levels in the cell lines that we have examined, although caspasedependent cleavage of CREB is observed in IR-sensitive leukemia cell lines.…”

Dietary potassium regulates vascular calcification and arterial stiffness

“…CREB is a target of cAMP signaling and is a widely expressed nuclear transcription factor that has been found to mediate the cellular response to metabolic and mitogenic signals (61). Activation of CREB signaling has been demonstrated in bone morphogenetic protein 9-induced osteogenic differentiation of mesenchymal stem cells (62).…”

The Hormonal Response of Estrogen Receptor β Is Decreased by the Phosphatidylinositol 3-Kinase/Akt Pathway via a Phosphorylation-dependent Release of CREB-binding Protein

“…ER␣ has been shown to be degraded through the proteasome pathway in a ligand-dependent manner (23,42), and blocking proteasome activity impaired the ability of ER␣ to mediate a transcriptional response to hormone (43)(44)(45), suggesting that ER turnover is necessary for receptor activity. Similarly, activation of the PI3K/Akt through platelet-derived growth factor stimulation of smooth muscle cells was shown to target CREB for degradation in a phosphorylation-dependent manner (46).…”