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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
BRAF is a serine/threonine kinase downstream from KRAS in the RAS– RAF–MEK–ERK–Mitogen-activated protein kinase (MAPK) pathway that is often altered in cancer [40]. RAS is a critical downstream effector of the epidermal growth factor receptor (EGFR). Stimulation of this pathway leads to a transient formation of the active, GTP-bound RAS. Mutant RAS proteins are insensitive to proteins that hydrolyze GTP to GDP and hence constitutionally activate downstream pathways. Activated RAS-GTP binds to RAF kinases leading to subsequent activation of MEK1 and MEK2 protein kinases, which in turn activate ERK1 and ERK2 MAPKs. Activated ERKs affect regulation of normal cell proliferation, survival and differentiation. ERK activation also promotes an autocrine growth loop that upregulates cellular expression of EGFR ligands resulting in tumor growth [40].
Effects of solar radiation, air pollution, and artificial blue light on the skin
Published in Roger L. McMullen, Antioxidants and the Skin, 2018
An example of a common proto-oncogene is the ras gene that encodes for the ras protein, a G-coupled protein that partakes in cell signaling by relaying signals from the growth factor receptor (at the plasma membrane) to kinases (cytosol), which eventually pass the signal to a transcription factor (nucleus) that promotes cell growth. When the ras gene is mutated (now an oncogene), the resulting ras protein becomes excessively active. In other words, it is able to signal downstream kinases without itself receiving a signal from the growth factor receptor. Thus, gene transcription relevant to growth is more active, leading to excessive cell division and proliferation.
Nonclinical Safety Evaluation of Drugs
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Thomas M. Monticello, Jeanine L. Bussiere
Over a decade ago, ICH guidelines allowed for an alternative approach to the traditional 2-year mouse carcinogenicity assay, that is, the conduct of a 6-month carcinogenicity assay in genetically engineered mice (ICH S1B 1997). On the basis of scientific rationale, the 2-year mouse study can be substituted with a 6-month transgenic mouse carcinogenicity study. The rasH2 and p53 transgenic mouse models have been the most widely used alternative models in the pharmaceutical industry. Transgenic rasH2 mice are hemizygous, carrying three copies of the prototype human c-Ha-ras oncogene with its own promoter (Tamaoki 2001). The ras protein has the potential to act as a potent carcinogen when expressed by the ras gene that has undergone mutations in certain critical domains. Overexpression of the normal ras gene also induces cell transformation. The rasH2 transgenic mouse model is responsive to both genotoxic and nongenotoxic chemicals. The general study design of the rasH2 carcinogenicity assay includes treatment groups of mice (e.g., 25/sex/group) with several different doses of the test agent and a negative vehicle control group. A positive control group may also be added, if scientifically necessary, to demonstrate the responsiveness of the rasH2 model to a known positive reference carcinogen (Long et al. 2010). In the validation process for this model, results of 6-month carcinogenicity studies demonstrated the rasH2 model to be equivalent or superior to the conventional 2-year mouse bioassay (Morton et al. 2002b; Storer et al. 2011).
Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design
Published in Expert Opinion on Drug Discovery, 2022
Kashif Haider, Anku Sharma, M Shahar Yar, Prasanna Anjaneyulu Yakkala, Syed Shafi, Ahmed Kamal
In human cells, major RAS oncogenes include KRAS, NRAS, and HRAS encode for KRAS (4A and 4B), HRAS, and NRAS, respectively. In RAS protein, the catalytic site has much higher similarity among all isoforms, which contains P-loop, switches I and II and RAS-effector interaction interfaces. RAS GTPases contain a CAAX motif, which serves as the substrate for a series of post-translational modifications. These modifications include initial prenylation by the covalent attachment of farnesyl pyrophosphate or geranyl pyrophosphate at the CAAX box (termed as farnesylation and geranylation, respectively), whereas HRAS can be only farnesylated. Most of the RAS proteins can be farnesylated and as well as geranylated. After prenylation, three-terminal amino acid residues (AAX) are removed at the endoplasmic reticulum. The carboxy group of terminal cysteine is methylated by an enzyme called isoprenylcysteine carboxymethyltransferase (ICMT). Except for KRAS4B, other RAS proteins then undergo palmitoylation at the adjacent cysteine residue and are transported to the plasma membrane by active vesicular transport [3]. Finally, the inner membrane of RAS activation is controlled through positive guanine nucleotide exchange factors (GEFs) and negative GTPase activating proteins (GAPs) (Figure 1) [4].
A Narrative Review of the Ocular Manifestations in Noonan Syndrome
Published in Seminars in Ophthalmology, 2022
Evita Evangelia Christou, Paraskevas Zafeiropoulos, Dimitrios Rallis, Maria Baltogianni, Christoforos Asproudis, Maria Stefaniotou, Vasileios Giapros, Ioannis Asproudis
It must be underlined that RAS genes constitute a multigene family. RAS proteins are small guanosine nucleotide-bound GTPases that function as a critical signaling hub within the cell; the inactive, GDP-bound RAS converts to its active GTP-bound form. Activated RAS proteins alter gene transcription and modulate function through a series of modifications. Therefore, dysregulation of the RAS/MAPK molecular pathway results in profound deleterious effects on developmental processes. Interestingly, due to a common underlying RAS/MAPK pathway pathology, the RASopathies exhibit overlapping phenotypic features. Additional mutations may affect specific locations of relevant genes resulting in distinctive phenotype. Indeed, while each syndrome in the spectrum of RASopathies has a unique phenotype, commonalities have been identified regarding the clinical characteristics. The phenotypic features may indicate a potential diagnosis, though clinical criteria have intrinsic limitations. We may not dispute that an initial clinical decision consists of challenging overlapping features and should in turn be confirmed by molecular genetic testing. Genotype-phenotype correlations may contribute to a better approach to the diagnosis of the syndromes and amelioration of treatment management in the future.5,13,20
Ras-Mediated Activation of NF-κB and DNA Damage Response in Carcinogenesis
Published in Cancer Investigation, 2020
There are now strong evidences that a few oncogenes such as Ras and c-Myc may be responsible in all three major stages of cancer i.e., early, intermediate and late (62,63). Ras is a G protein, or a guanosine-nucleotide-binding protein. The Ras protein family belongs to the class of proteins called small GTPase that are involved in cellular transduction transmitting signals within cells (Figures 2 and 3). This gene family consists of H-ras, K-ras, and N-ras which encode a 21 kD protein and possess guanosine triphosphate (GTP) activity (64–66). The molecular mechanism of Ras depends on the family of small G-proteins that function as signaling switches with active and “inactive” states. In the off state it is bound to the nucleotide guanosine diphosphate (GDP), while in the on state, Ras is bound to guanosine triphosphate (GTP), which has an extra phosphate group as compared to GDP. When released, the switch regions relax causing a conformational change in the inactivate state. Hence, activation and deactivation of Ras and other small G proteins are controlled by cycling between the active GTP-bound and inactive GDP-bound forms (67). The exchange of bound nucleotide is facilitated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GAPs accelerate Ras inactivation by activating its GTPase activity and GEFs catalyze a reaction, which releases GDP from Ras, thus GEFs facilitate Ras activation. The balance between GEF and GAP activity determines the guanine nucleotide status of Ras, thereby regulating Ras activity (68,69).