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Med One. 2018 Feb 25; 3:e180003. DOI:10.20900/mo.20180003.


Proponent Specificity as Targeting Evolutionary Traits in Ras Isoform Mutability in Carcinogenesis

Lawrence M. Agius1,2*

1 27 “Ballarat” Guzeppe Caruana Street, TAL-VIRTU, Rabat, RBT09 Malta, Europe;

2 Formerly of Department of Pathology, Mater Dei Hospital, TAL-QROQQ, University of Malta Medical School, Msida, Malta, Europe.

*Corresponding Author: Lawrence M. Agius, Telephone: 356-21451752, Email:

Published: 2/25/2018 15:32:24 PM


Distributional and re-distributional patterns of compartmentalization of RAS isoforms are core, persistently active abnormalities that are central/additional phenomena within mutable molecular structure and dysfunction in carcinogenesis. In such terms, ongoing transformations attributes, both within the plasmalemma and the internal membrane compartments, potentiate transformation, as further illustrated by sequestration of mutational forms of RAS. The incremental adaptation response of injured cells further conforms with the resultant dimensions of cooperating networks, rather than as linear pathways; these network organizations induce groups of neoplastic cells to further augment the effector end-target predispositions toward pre-carcinogenesis and carcinogenesis. RAS formulation is hence primarily an effector initiator and maintenance-inducing role-pattern formulator in carcinogenesis, as reflected in central metabolic pathways of cell growth promotion and proliferation.


RAS constitutes a series of family members of switching factors (including also N-RAS and H-RAS) that are dominantly subject to consequences of compartmentalization within the cytoplasm. KRAS is dysregulated in hepatocellular carcinoma, and in other neoplasm types, by loss of the tumor-suppressor microRNA-622[1]. Nrf2 (nuclear factor erythroid 2-related factor 2) enhances mutant K-ras/p53-driven pancreatic carcinogenesis[2]. Ras GAP (guanine-activating proteins)—related and C-terminal domain-dependent localization (and carcinogenic activities due to the scaffolding factor IQGAP1 that is involved in cell-cell adhesion, polarity and motility in melanoma cells) play a role in actin cytoskeleton dynamics during membrane ruffling and lamelliopodium protrusion[3]. It is further to such considerations that intra-cellular localization contrasts with a global series of roles of RAS in cell differentiation and growth-modulation. Substantial attributes of network multi-connectivity allow for the evolution placement of RAS in terms of the high cytosolic concentrations of GTP as compared with GDP. p19Arf (a well-established tumor suppressor) suppresses aggressive progression of H-RAS driven hepatocellular carcinoma and is either mutated or down regulated in a wide array of cancers[4].

The systems of evolutionary landmarks in the development of metabolic roles of RAS from fungal to mammalian species significantly confirm a central networking that is prominent in terms of the active roles of RAS bound to GTP. Chemotaxis, growth, survival and oncogenesis are activated by receptor tyrosine kinases and small G-proteins of the Ras superfamily that stimulate specific isoforms of phosphatidylinositol-3-kinase[5]. The membrane targeting role of the cytoplasmic tail of RAS is further confirmatory evidence that is manifested by sequestered by internal membranes and plasmalemma of the cell.

It is further to the roles of activation that mutations of the active core domain of RAS emerge to involve the consequences of a range of effector molecules and of adaptor molecules that thereby constitute a range of connectivity pathways. Nuclear Factor kappaB is implicated in human cancer initiation, progression and resistance to treatment; it acts as part of a node-network determining the patterns of effective targeting as expression of genes such as cross-talks with reactive oxygen species, p53, STAT3 and miRNAS[6]. Also, the residual functionalities of GTP-bound RAS and also of the GDP-bound RAS are central operators that essentially link the dimensional attributes of growth factors such as Epidermal Growth Factor and its receptor to downstream targets in oncogenesis. The two oncogenes KRAS and MYC cooperate to drive oncogenesis and MYC extensively programs immune-suppressive stroma in tumor progression[7] in terms of intra-nuclear interactions.


Compartmentalization of specific isoforms of RAS emerges as a central regulator in the exerted dimensional or global cellular dysfunction of RAS and of RAS family members. Attribute consignment allows for a distributional disarray in oncogenesis that further conforms to the assignment of binding and activating phenomena of cascade-induced impact.

Proportionality in mutability of RAS domains allows for the prominence of RAS alterations as the most common mutational abnormalities in oncogenesis. These may be present globally throughout most of the cells in the body or cells localised to specific organ systems. PTEN loss and activation of K-RAS and beta-catenin cooperate to accelerate prostate carcinogenesis[8]. In such panorama of distributions primarily within the cell cytoplasm, the impact of environmental stimuli transcends the effects of compartmentalization of RAS within systems of exerted stimulation of multiple transcribed genes. The development for further activation increases pathway dimensionality in terms of ongoing events linking the evolutionary course of actions within the cell. Several genetic and epigenetic alterations are collectively responsible for medullary thyroid and organ carcinogenesis, with RET, HRAS, and KRAS being the most important genes[9].

Post-translational modifications covalently bind fatty acid tails to specific amino acids and thus significantly alter the lipophilicity of the modified protein, and hence the anchoring to biological membranes[10].

KRAS is the prototype molecule family as canonical player in constituting further evolution in cell adaptability and response. Screening for K-RAS gene mutations is important in patients with colon polyps to thus provide possible personalised interventions targeting mutant K-RAS signaling pathways[11].

The Guanine Effective Factors are dimensionally positive stimulators in view of a release of the RAS molecule from GDP within a intracellular microenvironment that compounds the effects of maintained high concentrations of GTP.


The Golgi apparatus and the performance of vesicular formation and distribution perform the incremental effector attributes of intra-cellular trafficking in terms of the incremental performance of activated RAS. Isoform specificity adds further dimensional constitutional alteration of mutated RAS in a manner further conforming to pathways of targeted action.

Oncogenic mutations of RAS genes are found in approximately 30 % of human cancers and oncogenic RAS may induce non-apoptotic programmed cell death as a tumor suppressor mechanism in normal human epithelial cells[12].

Performance specification of RAS thus comes to evolve in terms of pathways of metabolism and also of cell survival and cell death pathway evolution. The use of antihypertensive agents targeting RAS, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can alter the incidence of renal cell carcinoma and also prolong patient survival[13]. It is further in terms of incremental activation that targeting pharmaceutics performs the significant roles for further transformation and this within a global scenario of cancer lesion maintenance.

In spite of deliverance and of adaptability, such attributes are permissive reflections of the overall dimensions for further growth response of cells within the essential occurrence of tumor invasion and spread and of metastatic lesions.


Effector pathways of the RAS hotspot mutations are reflections of the ongoing performance of incremental activation within series for further maintenance of the cancer lesion. These undoubtedly characterize the metastatic potentials for further growth and proliferation of the neoplastic cells. Transforming growth factor-beta (TGF-beta) inhibition suppresses hepatic tumorigenesis that is induced by activated RAS plus p53 down-regulation or by the co-activation of RAS and TAZ (a transcriptional regulator) signaling[14]. Indeed, the global network dimensions for significant distribution of mutated RAS molecules compound the effects of a distribution akin to non-linear pathway evolutions. RAS genes potentially enhance autonomous tumor cell division and survival and also may function in metastatic tropism as mediated by distinct chemokine sets signaling endothelial and myeloid cells[15].


Dysfunctional mutability of RAS isoforms emerges as the significant underlying performance of network connectivity within the additional roles of adaptor and effector pathways in terms of the continued global involvement of growth and differentiation of mammalian cells. It is further to continued cellular system activation that RAS mutability is central feature of such lesions as non-small-cell lung cancer and of lesions such as melanoma, colon and other organ neoplasms.

Lipid metabolism, glycolysis, enhanced pentose phosphate pathway. tricarboxylic acid cycle, citrate shuttle activity, bile acid synthesis and redox homeostasis in hepatocellular carcinoma as induced by Ras oncogene are significantly altered to induce carcinogenesis[16].

Significant mutability is a central attribute of pre-cancerous cells in terms of an evolution of cell organelle specificity. The contribution of the cancer microenvironment to the genesis of pancreatic adenocarcinoma is unclear, and this includes the development of stromal genetics in tumor initiation and progression[17]. The performance of activation as induced by GTP-binding allows for the reappraisal of end-site targeting that encompasses membrane function in terms of internal membrane dysfunction.


Dual-specificity of such systems as phosphorylation and of the ubiquitin-proteasomal systems progresses as modes of pathway effector targeting within the system formulations of incremental activation of RAS mutant molecules. Focal targeting is a specificity module that allows for global evolution in terms of system networks that include the carcinogenesis as transforming event in emergence of invasiveness attributes and of spread of the tumor cells. Indeed, the re-characterization of RAS isoforms include the specificities that emerge as effector modulators and as systems for targeting kinetics.

Systems of disarray and of dysfunctionality allow for the characteristic attributes of a neoplastic lesion that performs adaptor/effector response within signaling dimensions for further growth and spread. Ras-mediated skin tumorigenesis involves pathways that act through cyclin D1 and D2[18]. Distributional dysfunction is hence central core attribute in the performance of significant isoform specificity that gives dimensional and global attributes to individual cell disarray. The Notch pathway is involved in crosstalk signaling in gastric cancer and promotes Wnt, Ras and NF-kappaB pathways leading to carcinogenesis[19].


The performance of mutations and of mutability add to the isoform identity of lesional attributes within systems of cooperative adaptability as primarily evolutionary series of networks that perform dual, dysfunctional roles in effector targeting and transformation in oncogenesis. Patterns of adaptation, as exemplified by GEF (guanine nucleotide exchange factors) and GAP (guanine activating proteins) molecules, increase the scope performance of isoforms of RAS within the global disarray of membrane abnormalities of consequence. Intra-cellular dynamics perform trafficking dimensions that allow for emergence of system pathways that are specific network generators in cell injury response.

Dimensions of inclusive effect are regulated by both intra-nuclear dynamics and also as cytosolic turnover of MYC and RAS respectively. The role played by maintenance dynamics of various forms of mutant RAS are increasingly recognised within the further node dysfunctional pathways. Interactions with other member pathways and the cascade pathway stimulation induced by increased levels of mutant forms of RAS include the development of many cases of non-small-cell lung cancer and also of initiated transformation of colon epithelial cells. In such manner, K-Ras and N-Ras, in particular, mediate extensive network formulations in the further induced dimensions of such systems as endocytosis and maintenance of hyper-active targeting. The membrane-targeting hyper-variable domain of KRAS, in particular, indicates a hotspot mutability focus in induced network dysfunction that includes also negative feed-back control of cascade events.





















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