Subtractive library construction and differential screening were used to identify a cDNA for a cell type-specific immediate early gene induced in rat PC12 pheochromocytoma cells.
Cyclic AMP is a positive regulator of synaptic plasticity and is required for several forms of hippocampus-dependent memory including recognition memory. The type I adenylyl cyclase, Adcy1 (also known as AC1), is crucial in memory formation because it couples Ca(2+) to cyclic AMP increases in the hippocampus. Because Adcy1 is neurospecific, it is a potential pharmacological target for increasing cAMP specifically in the brain and for improving memory. We have generated transgenic mice that overexpress Adcy1 in the forebrain using the Camk2a (also known as alpha-CaMKII) promoter. These mice showed elevated long-term potentiation (LTP), increased memory for object recognition and slower rates of extinction for contextual memory. The increase in recognition memory and lower rates of contextual memory extinction may be due to enhanced extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling, which is elevated in mice that overexpress Adcy1.
Clinical studies involving patients with myelodysplastic syndromes or multiple myeloma have shown the efficacy of lenalidomide by reducing and often eliminating malignant cells while restoring the bone marrow function. To better understand these clinical observations, we investigated and compared the effects of lenalidomide and a structurally related analogue, CC-4047, on the proliferation of two different human hematopoietic cell models: the Namalwa cancer cell line and normal CD34 + progenitor cells. Both compounds had antiproliferative effects on Namalwa cells and pro-proliferative effects on CD34 + cells, whereas p21WAF-1 expression was up-regulated in both cell types. In Namalwa cells, the up-regulation of p21 WAF-1 correlated well with the inhibition of cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 activity leading to pRb hypophosphorylation and cell cycle arrest, whereas in CD34 + progenitor cells the increase of p21 WAF-1 did not inhibit proliferation. Similarly, antiproliferation results were observed in two B lymphoma cell lines (LP-1 and U266) but interestingly not in normal B cells where a protection of apoptosis was found. Finally, CC-4047 and lenalidomide had synergistic effects with valproic acid [a histone deacetylase (HDAC) inhibitor] by increasing the apoptosis of Namalwa cells and enhancing CD34 + cell expansion. Our results indicate that lenalidomide and CC-4047 have opposite effects in tumor cells versus normal cells and could explain, at least in part, the reduction of malignant cells and the restoration of bone marrow observed in patients undergoing lenalidomide treatment. Moreover, this study provides new insights on the cellular pathways affected by lenalidomide and CC-4047, proposes new potential clinical uses, such as bone marrow regeneration, and suggests that the combination of lenalidomide or CC-4047 with certain HDAC inhibitors may elevate the therapeutic index in the treatment of hematologic malignancies. [Cancer Res 2007;67(2):746-55]
(C1), another six-transmembrane domain (M2), and a cytoplasmic carboxy terminus of ~35 kDa (C2) (FIGURE 1B). The catalytic domain of adenylyl cyclases is hypothesized to be bipartite and split between C1 and C2 regions. The predicted size of mammalian adenylyl cyclases ranges from 110 to 130 kDa, but these proteins generally have an apparent molecular weight on SDS gels of ~200 kDa due to glycosylation in the extracellular loops of M1 and M2. Although the membrane topology and structure of adenylyl cyclases resemble transporters and ion channels, there is no evidence that these enzymes function as transporters or ion channels. However, cultured neurons express a voltage-sensitive adenylyl cyclase activity (25), suggesting that neurons contain an adenylyl cyclase or regulatory protein that is, like some ion channels, sensitive to membrane potential. AC1 is a Neurospecific Coincidence DetectorAC1 is the only neurospecific adenylyl cyclase identified thus far. It is expressed in brain, retina, and the adrenal medulla (45). Within the brain, AC1 is expressed in the hippocampus, neocortex, entorhinal cortex, cerebellar cortex, olfactory bulb, and pineal gland (29,45). AC1 expression in hippocampus increases dramatically during postnatal days 1-16 (31). The tissue specificity and developmentally regulated expression of the AC1 gene may be controlled by a 280-bp region and binary E-box like factor just 5Ј to the transcriptional start site (5). AC1 protein is detectable in the mossy fibers and the molecular layer of hippocampus and dentate in the macaque monkey, Macaca nemestrina (13), suggesting that AC1 is localized to axons in neurons of the hippocampus.Ca 2+ and CaM stimulate AC1 enzymatic activity with a half-maximal concentration of 150 nM free Ca 2+ , slightly above resting concentrations of Ca 2+ in neurons (43). CaM interacts with AC1 within the C1 loop region, close to the catalytic domain (43). The CaM-binding site within this region was identified by using peptide competitors and site-specifAdenylyl cyclases catalyze the conversion of ATP to cAMP, an important second messenger with diverse regulatory roles in the nervous system. Ten members of the adenylyl cyclase family have been identified by isolation of specific clones, each with unique regulatory properties and tissue distribution (for review see Ref. 46). In the brain, as in other tissues, adenylyl cyclases can be activated by receptor-coupled stimulatory G s proteins. For example, noradrenergic neurons of the locus ceruleus project to pyramidal neurons of the hippocampus and activate adenylyl cyclase through G s protein-coupled -adrenergic receptors (FIGURE 1). Two of the adenylyl cyclases, AC1 and AC8, are activated by Ca 2+ through the Ca 2+ -binding protein calmodulin (CaM). This review focuses on the CaM-stimulated adenylyl cyclases and their role in neuronal signaling, synaptic plasticity, and memory formation. These enzymes link activitydependent increases in intracellular Ca 2+ to the production of intracellular cAMP. Isolation and Structure o...
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