The Structure Of Protein P53 Biology Essay

The Structure Of Protein P53 Biology Essay Protein p53, encoded by gene Tp53, is known as a tumor suppressor. Discovered in 1979 as a transformation-related protein (DeLeo et al., 1979) and protein which accumulates in the tumor cells binding with simian virus 40 (SV40) large T antigens (Lane et al., 1979), p53 was regarded as an important protein in the regulation of an apoptosis and cancerization. During the last 30 years, a large amount of studies was taken in p53 and its related mechanisms in cellular process. In 1980s, researchers cloned the Tp53 gene and determined the role of p53 as a tumor suppressor. However, the structure of p53 protein was uncertain until 2006, in which William and his colleagues determined the DNA binding core domain of protein p53 (William. C. Ho. et al., 2006). Plenty of researches focus on the regulatory mechanism of p53 and hundreds types of targets and regulators of p53 were found, e.g. MDM2, Cyclin H, ATR, ATM, etc. These molecules can interact with p53 and regulate the life process collecti vely. P53 plays a very crucial role in cell cycle regulation and apoptosis induction, the mutation of p53 would lead to the cancerization in cells and induce cancer. Bai and Zhu (2006) reported that the mutation or loss of p53 gene and protein can be found in over 50% of tumor cells in human all around the world. For these reasons, the application of cancer therapy through protein p53 and Tp53 gene is a very potential aspect in cancer treatment. This review will describe the structure and function of p53 protein, examine its role in natural and tumor cells and focus on the cancer therapy application through p53. The Structure of P53 Human protein p53 is a 53KDa phosphoprotein encoded by a 20Kb-gene; it has an intricate structure which is closely related to its function. Wild-type P53 protein contains five major domains. The N-terminus of p53 is a transcription-activation domain (TAD), with a major one at residues 1-42 and a minor one at residues 55-75 (Venot et al., 1998). The basic function of this domain is involvement in the regulation of the pro-apoptotic transcription. Following the TAD is a proline-rich region which plays an important role in apoptotic activities. The central core of p53 protein is a DNA binding domain which can bind and interact with special DNA sequence that contain 2 copies of 10bp motif 5-PuPuPuC(A/T)-(T/A)GPyPyPy-3 (Kern et al., 1991). This region is also responsible for binding with LMO3, which is an essential co-repressor of p53 (Larsen et al., 2010). A nuclear localization signaling domain (NLS) is located beside the C-terminus of central core. The C-terminus domain of p53 protein, called negative regulatory domain is involved in the down regulation of DNA binding in central core (Chen, et al., 2005), and is also an essential part for the induction of cell death. A homo-oligomerisation domain (OD) located between the negative regulatory domain and NLS. This part is involved in tetramerization, which is a main activity for p53 in vivo. The different domains of p53 protein have their functions respectively, nevertheless, they constitute an inseparable entirety to play the role as a tumor suppressor. The function of p53 As a cancer suppressor, the main function of p53 is the anticancer function. P53 plays a vital role in apoptosis, gene stability and DNA damage through a series of complex mechanisms. First, p53 can respond to DNA damage through activating the DNA repair protein. For example, upon DNA damage, p53 gets activated and initiates the transcription of repair protein XPC and DDB2. The complex of p53-XPC-DDB2 can repair the DNA damaged by UV (Adimoolam and Ford, 2003). In addition, p53 can arrest the cell cycle at S, G1, and G2 phase (Agarwal et al., 1995), which can provide sufficient time for proteins repair to fix the damaged DNA. Induction of apoptosis, the programmed cell death, is also the essential and most important anti-cancer function of p53. If DNA damage is irreparable, p53 can activate the expression of pro-apoptosis genes like p21, Gadd45 (growth arrest and DNA-damageinducible protein 45), Bcl-2 family, etc. Moreover, p53 can bind and interact with hundreds of protein to regulate the cellular process and apoptosis. P53 can also restrain the cell cycle by repressing the expression of genes include bcl-2, bcl-X, cyclin B1, MAP4 and survivin (Bai and Zhu, 2006). The physiological functions of p53 are to maintain the genetic stability and regulate the normal cell cycle through a complex regulatory network. The mutation of Tp53 gene would lead to the loss of function of p53 protein, resulting in a cellular canceration. Consequently, the essential function of p53 is preventing the cancerization of cells by repairing genes or inducing apoptosis, in order to achieve these function, p53 can interact with a n umber of downstream targets. The Regulation in P53 Level A large amount of cellular response and process is induced by p53 through a series of complex biochemical mechanisms. P53 achieves its function through activating, binding, interacting with myriad kinds of downstream target molecules including kinase, enzymes, etc. Generally, p53 interacts with its target by phosphorylation of transcription-activation domain in N-terminus. The most well-known target of p53 is a cyclin-dependent kinase (CDK) p21. P53 would initiate the transcription and transduction of p21 in response to cellular stress, p21 is necessary in G1 control, the increase of p21 arrest the cell growth and induce cell death (Yin, et al., 1999). P53 and p21 contribute to a cell-cycle check point in G1 phase. The damaged genes would not be allowed to express until they are repair. If most damaged genes cannot be repaired, the accumulation of p21 regulated by p53 would induce apoptosis. Another important target of p53 is MDM2 (also called HDM2 in human body). MDM2 is a p53 inducible gene and its product can bind and interact with p53. The product of MDM2 gene, called p90 or p95, can bind with p53 and combine with ubiquitinate which can induce the degradation of p53 (Buschmann, et al., 2000). MDM2 is the killer of p53 which can keep the amount of p53 proteins into an appropriate level. However, a series of cellular stress would cause the overexpress of MDM2 and result in the over degradation of p53, the cell would lose ground and transform to tumor cell. P53 has plenty of other regulation pathways that cannot be listed in detail. The hundreds of pathways regulated by p53 have two mutual purposes: repair genes and induction of apoptosis. Therefore, the core of the p53 regulation levels is to maintain the stability of genes and accelerate the death of damaged or diseased cells. The Role of p53 in Normal and Tumor cells In natural human cells, the wt-p53 protein can be regarded as a guardian of the cell and genome. It can monitor the vital process, repair the gene indirectly through interaction with repair protein and induce apoptosis when necessary (Hofseth, et al., 2004). P53 plays a crucial role in numerous cellular processes which are related to cell cycle and cell death. If Tp53 gene mutated, the tumor suppression function in the cell would partly reduce. As a result, people whose Tp53 gene was mutated are more susceptible to suffer from cancer. Tp53 gene is mutated in over half of tumor cells; the mutation would alter the structure of p53 protein, thus p53 would lose its function partly or completely. The p53-mutated cells can not die programmatically, and become tumor cells. The mutated p53 protein tends to accumulate in tumor cells because the mutated p53 lose its function to induce the express of MDM2, which can degrade p53 proteins in the cell. The accumulation of p53 protein is a significant feature for the tumor cells. In cancer treatments, tumor cells can be detected through the accumulation of p53. However, mutated p53 can also be an obstacle of the therapy because mutant p53 can inhibit the function of wide-type p53 (Blagosklonny, M. V., 2002). If the treatment strategy is transferring the wide-type p53 into tumor cells, how to eliminate the effect of mutant p53 is the problem which has to be solved first. Consequently, p53 plays crucial roles both in normal cells and tumor cells; it is a gatekeeper in normal cells and a marker for tumor cells; it is an effective target for cancer treatments, nevertheless it can also become a barrier in cancer therapy. Conclusion P53 is the best-known transcription factor and cancer suppressor plays multiple roles in the cell. In healthy cells and, it is a gatekeeper to monitor the cell cycle and prevent the mutation of gene. If some mutations happen in the genome, p53 serve as a doctor to activate the repair process of damaged genes. When cells suffer from an irreversible damage or oncogenic stress, p53 can become a killer of cancerous cells. P53 participates in a number of biochemical pathways which can respond to the stress, arrest cell-cycle, repair gene and induce apoptosis. In the 30 years after the discovery of p53, plenty investigation was devoted into this essential protein and received a number of great achievements. A large amount of downstream targets has been identified and the regulatory network of p53 levels became clearer. Although plenty of details about p53, such as the relationship between each pathway, are still unknown. There is still a potential application through p53 in cancer treatmen ts.

A study of Arthur Conan Doyle’s Essay

Of the five Sherlock Holmes stories we have read, I will be writing about â€Å"The Silver Blaze†, â€Å"The Speckled Band† and â€Å"The Man With The Twisted Lip†. Sherlock Holmes, of 221 Baker Street is one of the most remarkable and remembered detectives of his time. Holmes is unlike any other fictional detective, as he seems almost too clever at times. Holmes is famous for his powers of observation and deduction. Holmes is able to change his age and gender in order to help solve a case but the image that sticks in most peoples head’s is of him in a ear-flapped traveling cap and with a pipe in his mouth Arthur Conan Doyle began writing the stories 100 years ago, he chose set them in the past times, although to him the stories were set in the present tence. I can tell the stories are set 100 years ago because of the language, clothing and transport. In each story Holmes is required to travel up and down the country in order to solve the cases. He often travels by 1st class carriage, this shows he is of the upper class and will appeal to the readers, as they too were probably upper class when the stories were first wrote. In â€Å"The Speckled Band† Holmes and Watson travel by Pony Trap, this is another type of old fashioned transport. Cars were not around at the time the stories were written, however if they were used this would spoil the story as it would ruin the setting. The old fashioned language also plays a key part in the setting, some of the words and phrases Holmes uses are no longer used in modern day society such as â€Å"Pray continue your narrative† and â€Å"alas† that are used â€Å"The Speckled Band†. In the Silver Blaze Holmes says â€Å"Helloa† not only is this old fashioned language but also is it slightly unorthodox for Holmes as his grammar is of a high standard. I think the setting appeals to the readers as there are no other old fashioned fictional detectives. In the modern day detective stories the detectives are not able to appear as clever as Holmes as they can solve their cases by taking D. N. A samples and matching them up with the suspects, leaving the hard work to science. As this sort of technology had not been invented while Holmes was alive, he had to solve the cases using only his intelligence and powers of observation. Each story is started in Holmes’s rooms, this too shows that Holmes was well off as houses in London were not cheap at the time. Another piece of evidence to show that Holmes was of the upper class is that he had his own maid that cooks and cleans, although Holmes is never seen eating. Although Holmes does not charge for his services, all of his clients are wealthy people. In â€Å"The Speckled Band†, Holmes’ client Mrs Hudson, lives in a large house in the country. The fact that all Holmes’ clients are wealthy and important shows that Holmes too is important and wealthy. If Holmes dealt with poor less important people or less challenging cases it would ruin his reputation and the story as it takes a complex case to make a good story. Of the three stories we have read, each has followed the same basic structure, the structure plays a key part in all of the stories, as it is the same throughout all of the stories it allows the reader to understand what is happening and to feel more involved as they know what will happen next. Each story starts with a brief comment from Watson, he will always try to make this case seem better than the previous one by saying things like â€Å"Of all these varied cases I cannot recall any which presented more singular features†. Here Doyle is trying to hook the reader into reading the rest of the story by making them believe that this story will be better than the last. The case will then begin with a troubled client finding Holmes, never the other way round, as Doyle does not want to make Holmes appear desperate by looking for clients. The client explains their case before leaving it for Holmes to solve. Although Holmes does not advertise his services in any way, his clients always find him, this is often because someone has recommended him. â€Å"I have heard of you from Mrs.  Farintosh, whom you helped in the hours of here sore need. † The fact that the client always finds Holmes largely adds to his reputation. There is one main difference in the opening of the stories, this is in â€Å"The Man with the Twisted lip† where start of the story is set at Watson’s house. The main difference here is that the client has not come to Holmes or Watson but to Watson’s wife, â€Å"Folk who were in grief came to my wife like birds to a light house† this also gives Watson a chance to explain the case to the audience before explaining it to Holmes. Conan Doyle has started the story like this mainly to give Watson a chance to shine and show that there are some differences in the structure of his stories. Although Watson is portrayed as being quite stupid, this is only because he is out shone by Holmes’ intelligence, Watson is in fact a doctor and although he does not solve any cases he does come to some significant conclusion. The next part of the story will involve Holmes and Watson traveling to the scene of the crime, which is a crucial part of the story. During their journey Holmes will often become â€Å"buried in the deepest thought†, here Holmes is already beginning to think of what may have happened before he has any real evidence. Although Holmes tries to distance himself from the police force his methods are exactly the same as that of the police. Each time Holmes visits the scene of the crime he is able to deduce more than anyone with him, often Watson. Holmes will then drop a red herring by offering a false conclusion, e. g.in â€Å"The Speckled Band† we are lead to believe that the gypsies are responsible for the murder as Holmes thinks this, at the end of the story we learn that the gypsies had nothing to do with the murder and that they were the red herring. The red herring is often the same conclusion that the readers and Watson had come too. In each story red herring is designed to throw the audience off the right trail. It offers a too-easy conclusion to the case, tempting us to take the bait and making fools of us if we do, although after reading a few stories we know that Holmes first conclusion will be a red herring therefore prompting us to discard it.

Returning to School

Returning to school after being out of school for 25 years can be a challenge in many ways. At times, it looks daunting and almost impossible. However, decisions like this are not made overnight. Neither are steps like this taken without some kind of preparation. Over time, there has been much physical, emotional and academic preparation. Physical preparation for this course was probably the easiest part of preparation.First of all, there has been research into to which college Is the best fit for the goals hat are desired to be obtained. In addition, several colleagues at work have returned to work and have told of the time that will be needed to obtain this goal. They have been an invaluable resource in telling how to physically Juggle working full time plus going to school. That has been the greatest preparation for the physical demands: Watching my colleagues. Other physical demands, such as computer needs, Internet connections, etc. Walden has been very good at being forth comin g about what is needed for those things. It is helpful to know how to structure life. Colleagues at work are helpful in knowing the best way to obtain books, sources to look for information, and other physical demands that will arise in this academic journey. To become emotionally prepared has been much more challenging. I had hoped that I would never have to return to school. I have obtained specialized trainings, certifications, and other skills with the hopes of not returning to school because It seemed like such a daunting task.However, for the past two to three years. I have started to see that the landscape of nursing is changing. I have realized that to continue to grow professionally and personally I am going to need my bachelor's degree. This realization of professional need has helped prepare me emotionally. I have spent the past two years looking into what is required to go back to school. I have also spent time observing how others who are my peers and who are also In sc hool observing are managing the process. I figured, â€Å"If they can do It, then so can l. It Is also a challenge to prepare academically. Tidying Is not a difficult task. For me, the hardest struggle has been to write a paper. In today's learning environment, the process is entirely online and majority of the process is about writing. My weakest subject has always been English. I have never used PAP format. Therefore, this thought Is single greatest component that has kept me from returning to school. It Is a great relief to spend time learning about the writing center and the resources they have to offer.I have spent time listening to the webzines and plan to access efferent parts of the writing centers help during my time at Walden. Other colleagues have told me of resources they have used to help them in this area. One day, at the pharmacy, even my pharmacist and her assistant offered to proof-read my papers for me! So, I feel like I have more support in these areas than I had at one time. Returning to school is a life altering decision. It takes lots of adjustment and much preparation. I am hoping that the preparation I have made In all ways- Alden university.

Modern Day Hobby Woodworking - 2163 Words

Woodwoorking Research Paper Woodworking is an excellent craft for all individuals. Woodworking has developed from an important necessity to a modern day hobby. Many Individuals rely on woodworking for income, shelter, transportation, and other necessities for survival. Woodworking is an excellent way to express ones creativity and skills. Woodworking is a fine art that is able to improve several factors of life if used correctly. Many individuals find woodworking appealing due to it’s usefulness and it’s lucrative ventures. Woodworking is an extremely reliable craft developed into an interesting form of art and architecture. Woodworking has become an international hobby that developed from ancient civilization. Many early civilizations†¦show more content†¦Many Woodworking tools were created in order to assist in crafting necessary materials. One example of a Woodworking tool is the chisel. A chisel is a woodworking tool used to cut into hard materials such as wood. The chisel was develop ed in order to assist individuals in creating art from wood and creating several useful items. There are several types of chisels including butt chisels, carving chisels, corner chisels, bevel edged chisels, and flooring chisels. Each chisel was designed for a specific purpose. The corner chisel was developed to clear out square holes in order to assemble furniture and structures. Each woodworking tool has very specific and important role in woodworking. In every early society they had certain goals in mind. The early societies reached these goals by developing tools that were required. In this process we gained many woodworking tools that we still use today. Many tools including saws, axes, knifes, and sander that were being developed carried great risk. Many Early societies found that several woodworking tools were very dangerous and began to develop safety measures. Woodworking can be extremely dangerous and requires precautions. Many woodworking tools have bladed moving parts. A pproximately 40,000 Americans seek emergency healthcare for injuries sustained while operating a table saw. In order to combat these accidents there are several safety standards that must be implemented.Show MoreRelatedThe Cultural Areas Of The Pacific Ocean2141 Words   |  9 Pagestraditional for a woman to have several husbands, but very rare for a man to have more than one wife. Polyandry was mainly practiced in the Marquesas Islands, but was practiced in several other Polynesian societies. Modern day (post-European), Monogamy is the widespread practice of Polynesia. Present day societies consent individuals the freedom to marry the partner of their choice. With the exception that same-sex marriage is technically illegal in Tahiti, though rarely ever acted upon by law enforcement.Read MoreEssay on The History Of Arts And Crafts5478 Words   |  22 Pagesof decorative or functional objects, generally by hand. Hand and power tools may be used, however, in making some craft item s. The term crafts also refers to the objects made. The function of crafts is generally concerned with crafts as creative hobbies, practiced primarily in the home with a minimum of specialized equipment. Crafts as so defined, have certain functions. In a world that is becoming increasingly mechanized and standardized, they give people the opportunity to work with their handsRead MoreChalk Out of Eggshells3296 Words   |  14 Pagesform  chert  or  flint  nodules  within the  carbonate rock Uses: * Blackboard chalk  is a substance used for drawing on rough surfaces, as it readily crumbles leaving particles that stick loosely to these surfaces. Although traditionally composed of natural chalk, modern blackboard chalk is generally made from the mineral  gypsum, often supplied in sticks of compressed powder about 4  in (10  cm) long. * Sidewalk chalk  is similar to blackboard chalk, except that it is formed into larger sticks and often colored. ItRead MoreIncome Taxation Solutions Manual 1 300300 Words   |  1202 Pagesindividual, the routine of life, and the existence of social and financial connections. If an individual does not have a continuing state of relationship, the individual may be deemed to be a resident if the individual is present in Canada for 183 days or more in a particular year [ITA 250(1)(a)]. Copyright  © 2013 McGraw-Hill Ryerson Ltd. Solutions Manual Chapter Three 11 Buckwold and Kitunen, Canadian Income Taxation, 2013-2014 Ed. A corporation is a resident of Canada if it has been incorporated