The notch protein is part of the greater picture, the notch signaling pathway. The actual protein serves as a trigger straddling the inside and outside of the cell membrane. When certain proteins bind to the exterior of the notch, the interior releases other proteins which make their way to the cell nucleus to alter gene expression. Some responsibilities delegated to the notch include but are not limited to cell proliferation, cell differentiation, and apoptosis.
Notch proteins are not an universal brand of amino acids, rather they are only found in Metazoans, or animals. Within these creatures, the variety of notch proteins range from notch-1 to notch-4. These notches correspond with five ligands termed Jagged 1, Jagged 2, Delta -1, Delta -2, Delta -3. When cancer or other diseases strike, the notch complex is usually deactivated, leading to a weak T-Cell response.
Typically, Notch is triggered primarily though direct contact, meaning that the external proteins must physically bind them to the exterior. Moreover, each individual cell that makes contact with the notch alters a different gene expression, so the process is very localized and specialized. For example, a particular cell would have to bind to the notch for a signal to activate apoptosis.
What is GSI?
GSI is a man-made pharmacological agent known to block notch activation. It works by inhibiting γ-secretase, an enzyme that cuts off the ends of proteins. Some viruses, like as HIV, must cleave proteins to function properly. With GSI, the HIV retrovirus is effectively prevented from reproducing, thereby halting the progression of the disease.
How GSI Inhibits KS
GSI inhibits the γ-secretase enzyme, which in turn prevents notch signals from reaching KS. Witho...
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Nude Mouse Model
Several mice were injected with SLK cells and were observed for 4-6 weeks. The mice tumors that had resulted were then directly injected with GSI while some were left untreated as controls. The animals were eventually killed from the tumors and their tumors were observed over time. It was discovered that the continuous injections of GSI caused pain for the animals. The pain was a minor problem that was solved by giving another dose of a chemical called buprenorphine (amount of 0.1mg/kg) helping the pain slowly go away. Even with the new chemical added, the results did not vary in any extreme manner.
Work Cited
Curry, C.L., Reed, L.L., Golde, T.E., Miele, L., Nickoloff, B.J., Foreman, K.E., 2005. Gamma Secretase Inhibitor blocks Notch Activation and induces apotosis in Kaposi's Sarcoma tumor cells. Oncogene 24, 6333-6344.
LJI308 is a potent and selective inhibitor of RSK. The p90 ribosomal S6 kinase (RSK) comprises a family of serine/threonine kinase which is expressed in various human cancers. RSK is the cytosolic substrate for the ERK (extracellular sianal-regulated kinase), involved in direct regulation of cell survival, proliferation, and cell polarity. Previous studies have demonstrated that RSK pathway is important for the growth and proliferation of cancer stem cells [1,2].
Although, it is easy to believe that all cells in a tumor are neoplastic, evidence suggests otherwise. There are three characteristics that are present in all KS cells whether they are neoplastic or not. The first is absence of a histologically distinguishable neoplastic cell. The second is the lack of usual chromosomal abnormalities. The last is a combination of three features angiogenesis, inflammation, and proliferation.
Specifically “TP53, p16INK4A, and SMAD4. The p53 nuclear protein activates transcription of a cyclin kinase inhibitor p21WAF1/CIP1. Following genomic stress, inappropriate growth factor stimulation or expression of oncogenic ras increased expression of p53, and thus p21WAF1/CIP1 resulted in inactivation of specific CDK/cyclin complexes” (MedScape). If this transformed cell can escape internal and external fail-safe mechanisms, receive nutrients, and activate its proliferative program, it can form a mass of cancerous cells. Tumor growth can cause the loss of pancreatic functions. Another characteristic of pancreatic cancer is metastasis happens early in tumor growth, which is most likely responsible for pancreatic cancer’s aggressive
receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things
The cancer stem cell theory hypothesizes that tumors or cancers arise from mutations or epigenetic changes in normal stem cells. These mutated or genetically altered stem cells possess the properties of the normal stem cells such as the ability to self-renew, differentiate into any type of body cell, and resist apoptosis. Hence, the cancer stem cells (CSC) are named so. It is also suggested that because of the above-mentioned properties of the cancer stem cells, the current anti-cancer therapies are not entirely successful (Gil et al, 2008). Despite surgery and other therapies, even if very few of these cancer stem cells survive, they can continue to act as a source for more tumors, even though the therapies eliminate all visible signs of cancer.
The article begins by stating that the tumor suppressor p53 has great importance in the prevention of cancer growth and expansion. Although cancer is the most spoken about topic and p53’s significance against it, p53 also has a hand in ischemia, neurodegeneration, and ageing. While this tumor suppressor seems to be very busy it also regulates the repair of DNA and death of the cell, just to name a few. The activity of p53 can be seen when binding to the DNA at target sequences for transcription. It was pointed out that the doings of p53 are not designated to the nucleus such as other transcription factors as determined over time. Further mentioned in the introduction is a statement that lists this as the most studied mechanism while also related to the material covered in class is apoptosis. P53 inducts apoptosis in the by intrinsic mitochondria-mediated pathway, also transcriptionally through pro-apoptotic parts of the pathway, and in a transcription–independent way which has been recently been looked further into. As if the roles above were not plentiful enough cytoplasmic p53 is also thought to influence autophagy, movement of vesicles, signal transduction, cell metabolism and possibly stem cell expansion, but all are truly determined. Towards the end of the introductory section the authors state that there are still many mechanisms of cytoplasmic p53’s activation leading to apoptosis that are uncertain as well as some p53 missense mutants that lead to oncogenesis. The authors express that the article mainly will speak about the proper or improper activities performed by p53 on the mechanism in the cytoplasm while also looking for areas where beneficial treatments may be used.
Transcription factors allow cells to perform logic operations and combine different sources of information to "decide" whether to express a gene.
In some organism PDK 2 activates AKT by phosphorylating it at S473 sequence in regulatory domain. Activated ATK further regulates many cellular downstream processes (Fig 2).
Similarly, cancerous lymph node associations cause promoter hypermethylations, which overexpress Twist1.2 Through that overexpression, the WR domain (N-terminus of Twist1) binds to the transcription factor complex responsible for post translational modifications, called RELA (NF-kB subunit).2 Then, an activated RELA promotes the epithelial-to-mesenchymal transition (EMT) in a downstream pathway.1 Considering EMT regulates cancer cell metastasis, overexpression results in upregulation of EMT effectors N-cadherin and vimentin, with the downregulation of EMT effector E-cadherin (Fig 2).7 Consequently, the alteration in regulation patterns of the EMT effectors induces cellular intrusion and metastasis (Fig. 2).
Some medication that slice oncogenes measure already been manner, and additional measure on the approach. This can be mentioned in additional detail presently during this monument. A few cancer syndromes measure caused by hereditary mutations of proto-oncogenes that (cancer.org, 2014)supply the CELL to be formed on (activated). For case, multiple endocrine pathologic process image two (MEN2) is caused by a chromosomal mutation within the factor designate. Individuals hooked up by this syndrome typically develop a rare thyroid cancer referred to as medullary cancer of the thyroid. They (cancer.org, 2014)conjointly develop different tumors, embrace tumor and nerve tumors.
The cell cycle is the process by which cells progress and divide. In normal cells, the cell cycle is controlled by a complex series of signaling pathways by which a cell grows, replicates it’s DNA and divides, these are called proto-oncogenes. A proto-oncogene is a normal gene that could become an oncogene due to mutations. This process has mechanisms to ensure that errors are corrected, if they are not, the cells commit suicide (apoptosis). This process is tightly regulated by the genes within a cell’s nucleus. In cancer, as a result of genetic mutations, this process malfunctions, resulting in uncontrolled cell proliferation. Mutations in proto-oncogene or in a tumour suppressor gene allow a cancerous cell to grow and divide without the normal control imposed by the cell cycle. A change in the DNA sequence of the proto-oncogene gives rise to an oncogene, which
Cancer has been seen in humans as one the most potentially fatal disease for thousands of years and only in the recent couple of hundred years have we discovered that most information necessary to bring us to today’s understanding and knowledge (Kenny 2007, Weinberg 1996) was achieved by extensive research of cells, DNA, and epidemiology studies. As we know, currently cancer is acknowledged as having over a hundred different diseases, and is known to be the result of mutations of the genes and almost similar DNA which are responsible for the amount of cell division and production (Kenny 2007). Restraint of cell growth modulators can be a direct lead and result of certain tumours being developed and subsequently allow these tumours to acquire the ability to attack and occupy the bloodstream and essentially be able to travel via the bloodstream to other parts and organs in human bodies which is known as metastasis (Loeb et Al 2003). Once this has occurred , the cancer is then categorized as malicious and becomes a dangerous and serious threat to the carrier (Weinberg 1996). In this essay I will describe and explain the process of this and how our genes mutate and lead to metastasis of cancer cells.
4.) Mainardi, Paola. "Abstract." National Center for Biotechnology Information. U.S. National Library of Medicine, 5 Sept. 2006. Web. 29 Nov. 2013. .
Over time there has been the discovery of many different type of cancer, which all begins in cells, that can be classified as a body’s form of basic building blocks. Cancer cells are essentially cells that have gone wrong, meaning they no longer generate responses to the signals, which control the human cellular developments. Cancer cells have a complex nature, due to its combination of various abnormalities that results in normal cells becoming cancer cells. Over time, cancel cells are developed within tissues and, as the tissues grow the cells grow and divide, resulting in the cells becoming resistant towards the signals that maintain the normal tissue production. In the final stages of cancer, the cancer cells are capable of breaking through normal tissue boundaries and metastasizing throughout the body.
For years people have been looking for a cure for the devastating disease of cancer. Cancer is the third highest killer in the US with over 2,500,000 victims per year. Oncologists and scientists around the country are researching all forms of cancer in an effort to understand, treat, and ultimately defeat this disease. Already there have been numerous advances in the field, such as chemotherapy and gene therapy. One advance has been the use of a cell process known as apoptosis. By harnessing this normal cell process, scientists hope to have found an effective way to combat cancer.