Interrogation of the Drosophila Genes for Enzymes Regulating Ras Signaling During Eye Development. This study aims to review literature regarding the Ras gene. The role of this gene in the development of cancer has been proven through several studies in the past and it is now referred to as Ras proto-oncogene. The expression of this gene is under the influence of enzymes and this study aims to find out whether any mutation of this gene has a role to play in cancer. Homologs of this mammalian gene are present in Dorsophila. Since this organism is convenient for use in labs due to its size and ability to be simulated easily, the Dorsophila is used.
The development of the eye of the Dorsophila is used in this study to assess the role of Ras gene in cellular proliferation. Assessment of this role can help guide more targeted pharmaceutical interventions as the current medications against cancer have multiple side effects which often lead to complications. Not only is this review beneficial to those researchers who are conducting similar studies but it could also be useful for people who have been funding these researches in assessing how far there valuable resources have taken us in identifying the genetic etiology of cancer related to Ras proto-oncogene.
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Cancer is a major health burden on living populations across the world. The number of deaths due to cancer has risen to alarming rates. According to recent statistics, estimated new cases of cancer in US during 2010 are around 1,529,560 whereas the deaths due to cancer are nearly 569,490 (American Cancer Society, 2010). Not only is this due to increased exposure to carcinogens in everyday life but also due to better diagnostic abilities that can detect cancerous development in very early stages. Regardless of whether a cancer is preventable or not or whether it can be treated or not, cancer remains to be one of the most feared and severe diseases worldwide.
In recent years, a lot of efforts and finances have gone into discovering the mechanisms behind the development of cancer. The aim of these studies has been not only to understand the disturbances within cellular growth mechanisms but also to develop effective preventive measures, screening techniques and targeted pharmaceutical treatments.
The development of cancer is an extremely complex process and involves multiple factors interacting with each other to render defective growth control mechanisms. It involves genetic mutations, presence of carcinogens, presence and expression of oncogenes and the character of enzymes that regulate the genetic expression and resulting proteins. These factors work together to modulate the cell signaling pathways allowing uncontrolled proliferation of cells. Thus the major defect that leads to the development of cancer is a defect in the cell signaling pathways as proven by several studies using biochemical and cellular essays and cloning techniques. However the complexity of the interactions leading up to this defect has prevented an exact mechanism to be known. Several oncogenes have been identified to have been responsible for cancers of several types. One of the first oncogenes to have been identified was the Ras oncogene. Homologs of this gene are present in the Dorsophila and regulate the development of the eye. This research paper aims to study the mechanism through which Ras signaling pathways regulates the development of eyes in Dorsophila in order to develop a better understanding of the mechanisms used by this geneâ€™s mammalian homologues.
What is the role of Ras signaling pathway in cancer?
What are the regulatory and modulatory mechanisms of the activity of Ras signaling pathway in Dorsophila?
What are the therapeutic options for blockage of enzymatic proteins that regulate the signaling pathways?
Intensive research has been conducted in order to understand the development of cancer. Cancer has three components, initiation, promotion and progression(Pitot, et al., 1991). The first two components involve the interaction of initiators and promoters with DNA causing qualitative changes or mutations. Similarly Clark divided the development of cancers into 4 stages (Clark, 1991). Each one of these stages was different from the rest as it required a different DNA mutation which resulted when DNA interacted with initiators and promoters. These stages are characterized by the progression of a cancer from a benign to a metastatic cancer. In all of these models, the central fault lay within the cell signaling pathways which controlled cell growth proliferation, differentiation and growth.
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The Rasgene product was the first protein to be identified as a critical agent in the proliferation of cells. This protein is found in two states; an active GDP-bound inactive state and a GTP-bound active state (Manne, et al., 1985). Cell surface receptors remove GDP and replace it with GTP activating GTPase leading to activation of Ras which acts as a molecular signal in initiating a string of reactions which involves phosphorylation and activation of mitogens. These reactions eventually lead to cell proliferation. The Ras signaling pathway is a self-limiting pathway in normal conditions. However, mutations in the Ras gene lead to continuous activation of Ras gene which results in uncontrolled cellular proliferation. This uncontrolled proliferation is the hall mark of cancer.
The Ras gene is actually a group of three functional genes, H-Ras, K-Ras and N-Ras. Most human tumors show a mutation of at least one of these genes. These genes are susceptible to point mutations leading to single base substitutions. The cancers that show the highest incidences of Ras mutations include carcinomas of pancreas, colon, lung, thyroid and myeloid leukemia.
Programme and methodology
Literature regarding the Ras gene signaling pathway and its role in the development of the eye of Dorsophila will be studied. Since Ras gene has been proven to play a crucial role in the development of cancers, it is being investigated. Dorsophila has been chosen due to two reasons. Firstly, the cells of the Dorsophila possess genetic homologues of mammalian Ras genes. Secondly, Dorsophila are easily simulated and predicted and are very suitable for lab procedures. The Dorsophila eye is a compound of 800 ommatidia with each containing 8 photoreceptors. Each photoreceptor can detect different wavelength of light including UV light (Brody, 1996). These photoreceptors develop from R8 to R7during the embryonic period and the differentiation of R7 photoreceptor precursor is controlled by the Ras signaling pathway. The enzyme that plays a key role in Ras signaling pathways in mammals is SIAH while its parallel in Dorsophila is Seven-In-Absentia (SINA) and the activity of this enzyme is very important in detecting the expression of Ras gene.
The study has to be conducted keeping in mind all the possible effects that Ras gene mutations can have on cancer development. A very important part of understanding the role of Ras gene in cancers is to find evidence of the effect of misexpression of this gene. It is the misexpression of this gene that eventually leads to uncontrolled proliferation of the cell.Secondly, we need to be able to see the effect of promoters on the Ras gene. From earlier studies, we know that when it comes to carcinogenic mutations, the effect of initiators is very slow while the effect of promoter is very quick. As a result the length of the study will be shortened and easily monitored. Not only is it important to monitor the overexpression of the Ras gene but it is equally important to monitor the effect of this silenced gene on carcinogenesis.
Since this study is being conducted on Dorsophila but is aimed at finding the role of Ras gene mutation in carcinogenesis in mammals, we need to be able to draw genetic similarities between the cells of the two species and identify parallel systems that are a part of signaling pathways in each of the species.
Over the years intense research has not only led to new discoveries but also to the development of sophisticated investigative techniques. This field developed at an exceptionally fast pace once the world of genetics was open to us.
Keeping in mind, the factors that we are looking for in our study, certain experimental techniques will be used that will provide evidence of the role of Ras gene in the development of cancer.
For our first investigation, we will need to target the Ras gene expression using GAL4. GAL4 was identified in a strain of yeast and since then has become a very useful tool in assessing overexpression or misexpression of targeted genes (Phelps, et al., 1998). This is particularly true for in vivo studies. By applying this on Drosophila, it is also possible to identify phenotypes and genetic interactions relevant to mammals. Thus, it also serves as a screen.
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For our second investigation, we will require special constructs of UAS-Ras V12 Drosophila transgenic lines in order to assess the effect of certain substitutions within the Ras protein. Although the mammalian systems may show a different response to these mutations, the Drosophila is a very close comparison.
The third investigation requires genetic modifiers screens and engineered enhancer element inserts. Not only can these screens show mutations but also show relevant biological phenotypes and genetic markers that are common between the Drosophila and the mammals. This can reduce the suspected difference in the effect of Ras mutations between Drosophila and mammals.
For our fourth investigation, we will require the silencing of Ras gene which will be done through transgenic UAS-RNAi. This is a highly targeted technique that degrades target mRNA thereby silencing the gene. However, the use of this technique causes partial silencing of the gene in Dorsophilabut is still used because it provides a rough but quick result at low cost.
Impact of my research
Cancer is a global disease affecting hundreds of thousands of people across the world each year. My research aims to discover one of the pathways that allow it to do so. The defect within cell signaling pathways due to Ras gene mutation has been a focus of cancer research for several decades and any contribution to this work has a considerable impact on several quarters of life. Not only will this research be helpful to clinicians and pharmaceuticals in developing medications and treatments that target specific mechanisms, it will also help the funding agencies of similar studies in realizing their immense contribution to health and science and the need for their continued assistance.