1, the major targets of cAMP include PKA, Epac1 and Epac2, and nucleotide-gated ion channels. The concentration of intracellular cAMP depends on the relative balance between adenylyl cyclases and phosphodiesterases.Īs shown in Fig. So far, at least 22 PDEs have been identified. In contrast, phosphodiesterases (PDEs) are responsible for the degradation of cAMP. In addition, bicarbonate (HCO 3 −) and calcium ions (Ca 2+) induce cAMP synthesis by activating the soluble adenylyl cyclase (sAC) independent of G-proteins. After extracellular ligands, such as PGE2, GLP-1 and β2 receptor agonists, bind to G-protein coupled receptors (GPCRs), Gα subunits are separated from Gβ and Gγ subunits, and then activate adenylyl cyclases (ACs), leading to the conversion of ATP into cAMP (Fig. The generation of cAMP is regulated in a G-protein-dependent or G-protein-independent manner. Therefore, cAMP can directly regulate various biological processes or behaviors of cells, including cell metabolism, ion channel activation, gene expression, cell growth, differention and apoptosis. Many hormones, neurotransmitters and other signaling molecules use it as intracellular second messenger. Notably, cAMP–PKA–CREB signaling has both tumor-suppressive and tumot-promoting effects on cancer, depending on the tumor types and context.ĬAMP exists extensively in cells. As one of the target proteins of PKA, cAMP response element binding protein (CREB) is an important transcription factor that regulates the expression of several genes including oncogenes c-Jun and cyclin D1. As a second messenger, cAMP is responsible for activation of the protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac) and ion gated channel protein. The second messenger theory was first proposed by E. Abnormal production and distribution of these second messengers may contribute to carcinogenesis and tumor progression. In general, the production and distribution of these second messengers also need precise regulation. This process involves multiple feedback mechanisms as well as a number of intracellular chemicals, known as the second messengers, such as cyclic adenosine monophosphate (cAMP), cGMP, calcium ions and so on.
CYCLIC AMP OFTEN CAUSES ACTIVATION OF SERIES
Ĭell signaling is often initiated by first messengers such as growth factors, hormones and ions, which trigger a series of signal transduction cascades via membrane receptors or intracellular receptors. Later on, inhibitors of protein kianses such as EGFR, ErbB2, MAPK, VEGFR and mTOR have been widely used in the treatment of a variety of common malignant tumors.
As an inhibitor of the oncogenic kinase BCR–ABL, imatinib is the first kinase-targeted anticancer drug that has been successfully applied in the treatment of chronic myeloid leukemia. Abnormal or uncontrolled activation of protein kinases or phosphatases is very common in tumors, poising them as important targets for molecular targeted cancer therapeutics. Protein phosphorylation and dephosphorylation are regulated by various protein kinases and phosphatases, respectively. Posttranslational protein modifications, such as phosphorylation, ubiquitination, methylation and acetylation, are one of the important mechanisms that regulate cell signaling. Abnormal activation or inhibition of signal transduction pathways drives tumorigenesis. Cell growth is tightly regulated by a variety of signal transduction pathways.
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