It is encoded by the Rb gene and serves an important role as a tumor suppressor (118). used as potential targets for the treatment of UMs. and Apaf-1 assemble the apoptosome which activates caspase-9 (38). Alongside caspase-9 activation, caspase-3 is activated, leading to the same steps as the aforementioned extrinsic pathway (39). The Bcl-2 family proteins, which are directly controlled by p53, determine the cell fate through the balance of pro- and anti-apoptotic molecules (38). The molecular and genetic makeup of UMs is considered to be more complicated than the aforementioned mutations. Therefore, the present review will explore the potential role of multiple molecular pathways and their role in UM development and pathogenesis. 4.?G protein subunit q and G protein subunit 11 Despite the chromosome abnormalities, most UMs are considered to be caused by point mutations in G protein subunits, specifically in G protein subunit q (GNAQ) and G protein subunit 11 (GNA11), regardless of tumor stage or chromosomal constellation (40). These mutations have similar effects as mutations in RAS, which are common in a number of other tumors (41). The G- subunit is important due to its involvement in multiple essential cellular pathways, such as the MAPK (cell proliferation and apoptosis), PI3K-Akt (growth ACT-335827 and homeostasis) and Hippo signaling pathways (42). GNAQ and GNA11 activate phospholipase C, which triggers a cascade of events resulting in the activation of protein kinase C (PKC). PKC then initiates a phosphorylation cascade, which activates Raf, MEK1/2 and ERK (43). This process results in the regulation of cell proliferation and survival (44). It has been hypothesized that these mutations are early events in the pathogenesis of UM and are necessary for tumor malignancy (45). On the other hand, mutant GNAQ and GNA11 are considered to be weak oncogenes and, therefore, cannot cause damage to melanocytes unless they are already deficient in the p53 and p16/CDK4/RB signaling pathways (46). Due to the importance of GNAQ and GNA11 in UM malignancy, the 5-oxo-ETE acid G-protein-coupled receptor 1 (GPCR) signaling pathway is a potential viable therapeutic target (42). The development of inhibitors for specific molecules, such as Gq/11 inhibitor YM-254890 and Arf6-inhibitor NAV-2729, is one of the main strategies that is currently being investigated (47,48). Mmp28 One such example is the inhibition of CysLT2R-L129Q, which is responsible for the constitutive activation of the Gq/11 signaling pathway in UM (47,49). 5.?RAS interactions The Ras superfamily consists of small GTPases that act as switches ACT-335827 and modulate a vast array of cell functions by influencing signaling pathways. They are separated into six different groups of proteins, and are present in all cell types (50). One of the subfamilies, also referred to as RAS, consists of proteins that regulate cell proliferation. They have downstream effects on signaling pathways crucial to UM, such as the MAPK/ERK and PI3K/AKT/PTEN signaling pathways (51). In cancer, RAS is often mutated which affects a number of these pathways and makes them less sensitive to apoptosis triggers, thus increasing proliferation levels (Fig. 1) (52). Open in a separate window Figure 1. Outline of the key molecular signaling pathways affected in UM discussed in the present review article. The present review explored the typical UM abnormalities starting from the cytoplasm and moving to the nucleus. Firstly, RAS regulates the PI3K/Akt and Raf/MEK/ERK signaling pathways (left). Subsequently, the present review explored apoptosis involving p53/MDM2, and the regulation within the nucleus, including cyclins and cyclin-dependent kinases. MDM2, MDM2 proto-oncogene; UM, uveal melanoma. All three common RAS proteins in humans are highly conserved in the active regions and often undergo mutations in codons 12, 13 and 61 (53). The resulting point mutations lead to preferential binding to GTP over GDP, which in-turn leads to activation of proliferation pathways (54). Interestingly, RAS mutations are not usually associated with UM (55,56). In general, RAS serve as activating proteins that remove GDP and allow GTP to bind its target (57). Ras-bound GTP goes on to activate Raf, which initiates the MAPK/ERK signaling pathway (58). In the case of PI3K, active Ras directly.If toxic chemicals, oxidative stress (reactive oxygen species), ionizing radiation and other factors induce DNA damage, the cell must repair it and reenter the cell cycle (102). caspase-9 (38). Alongside caspase-9 activation, caspase-3 is activated, leading to the same steps as the aforementioned extrinsic pathway (39). The Bcl-2 family proteins, which are directly controlled by p53, determine the cell fate through the balance of pro- and anti-apoptotic molecules (38). The molecular and genetic makeup of UMs is considered to be more complicated than the aforementioned mutations. Therefore, the present review will explore the potential role of multiple molecular pathways and their role in UM development and pathogenesis. 4.?G protein subunit q and G protein subunit 11 Despite the chromosome abnormalities, most UMs are considered to be caused by point mutations in G protein subunits, specifically in G protein subunit q (GNAQ) and G protein subunit 11 (GNA11), regardless of tumor stage or chromosomal constellation (40). These mutations have similar effects as mutations in RAS, which are common in a number of other tumors (41). The G- subunit is important due to its involvement in multiple essential cellular pathways, such as the MAPK (cell proliferation and apoptosis), PI3K-Akt (growth and homeostasis) and Hippo signaling pathways (42). GNAQ and GNA11 activate phospholipase C, which triggers a cascade of events resulting in the activation of protein kinase C (PKC). PKC then initiates a phosphorylation cascade, which activates Raf, MEK1/2 and ERK (43). This process results in the regulation of cell proliferation and survival (44). It has been hypothesized that these mutations are early events in the pathogenesis of UM and are necessary for tumor malignancy (45). On the other hand, mutant GNAQ and GNA11 are considered to be weak oncogenes and, therefore, cannot cause damage to melanocytes unless they are already deficient in the p53 and p16/CDK4/RB signaling pathways (46). Due to the importance of GNAQ and GNA11 in UM malignancy, the 5-oxo-ETE acid G-protein-coupled receptor 1 (GPCR) signaling pathway is a potential viable therapeutic target (42). The development of inhibitors for specific molecules, such as Gq/11 inhibitor YM-254890 and Arf6-inhibitor NAV-2729, is one of the main strategies that is currently being investigated (47,48). One such example is the inhibition ACT-335827 of CysLT2R-L129Q, which is responsible for the constitutive activation of the Gq/11 signaling pathway in UM (47,49). 5.?RAS interactions The Ras superfamily consists of small GTPases that act as switches and modulate a vast array of cell functions by influencing signaling pathways. They are separated into six different groups of proteins, and are present in all cell types (50). One of the subfamilies, also referred to as RAS, consists of proteins that regulate cell proliferation. They have downstream effects on signaling pathways crucial to UM, such as the MAPK/ERK and PI3K/AKT/PTEN signaling pathways (51). In cancer, RAS is often mutated which affects a number of these pathways and makes them less sensitive to apoptosis triggers, thus increasing proliferation levels (Fig. 1) (52). Open in a separate window Figure 1. Outline of the key molecular signaling pathways affected in UM discussed ACT-335827 in the present review article. The present review explored the typical UM abnormalities starting from the cytoplasm and moving to the nucleus. Firstly, RAS regulates the PI3K/Akt and Raf/MEK/ERK signaling pathways (left). Subsequently, the present review explored apoptosis involving p53/MDM2, and the regulation within the nucleus, including cyclins and cyclin-dependent kinases. MDM2, MDM2 proto-oncogene; UM, uveal melanoma. All three common RAS proteins in humans are highly conserved in the active regions and often undergo mutations in codons 12, 13 and 61 (53). The resulting point mutations lead to preferential binding to GTP over GDP, which in-turn leads to activation of proliferation pathways (54). Interestingly, RAS mutations are not usually associated with UM (55,56). In general, RAS serve as activating proteins that remove GDP and allow GTP to bind.