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== Overview ==
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== Introduction ==
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<scene name='C-Myc/Custom/2'>TextToBeDisplayed</scene>
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<scene name='Kwon_sandbox/C-myc/1'>c-Myc</scene> is a protein that binds to DNA and regulates transcription, a transcription factor. Bishop and collegues discovered viruses that induced chicken sarcomas. They studied the virus and identified an oncogene that would cause uncontrolled cellular proliferation. The viral oncogene that caused the sarcomas was identified as v-myc. Later on the homologous gene in chickens was discovered, and called c-myc. These findings provided evidence that activated c-Myc proteins were significant in cellular growth regulation.
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The c-Myc [http://en.wikipedia.org/wiki/Oncogene oncogene] encodes a [http://en.wikipedia.org/wiki/Transcription_factor transcription factor], c-Myc protein, which is involved in the regulation of the [http://en.wikipedia.org/wiki/Cell_cycle cell cycle]. C-Myc belongs to the [http://en.wikipedia.org/wiki/C-myc Myc] family of proteins including B-Myc, L-Myc, N-Myc, and s-Myc. c-Myc is a [http://en.wikipedia.org/wiki/Basic_helix-loop-helix_leucine_zipper_transcription_factors b-HLH-LZ] (basic helix-loop-helix-leucine zipper) protein that must form a [http://en.wikipedia.org/wiki/Heterodimer heterodimer] with another b-HLH-LZ protein, [http://en.wikipedia.org/wiki/MAX_(gene) Max], in order to bind DNA and activate [http://en.wikipedia.org/wiki/Transcription_(genetics) transcription].
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==Role in Cancer==
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Mutations in myc proteins or overexpression of their encoding genes have been linked to several forms of cancer, among these are lymphoma, myeloma, liver, lung, and breast cancer.
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[[Image:800px-Signal transduction v1.png|Apoptosis signal pathway|400 px|thumb]]
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c-Myc is further along in the signal transduction pathway of the epithelial growth factor receptor (EGF receptor) which deals with the proliferation of cells. Mutations of c-Myc have a strong correlation to cancer. Normally c-myc is tightly regulated and c-Myc is short lived, but cancer cells express c-myc uncontrollably and are unable to degrade the c-Myc protein. This over expression and inability to rid the protein causes it to be active much longer. thus causing the over expression of genes needed for cell proliferation causing cancer. Over expression of c-Myc is prevalent in 80% of brest cancers, 70% colorectal cancers, 90% of gynecological cancers, 50% of hepatocellular carcinomas and is particularly prevalent Burkitt’s Lymphoma.
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==Research of Structure and Function==
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[[Image:C-Myc-DNA complex.png|c-Myc Dna complex|400 px|thumb]]
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There are two main structures of the c-Myc proteins that are significant in its function. These are the Thr58 sight and the helix-loop-helix (HLH) motif surrounded by a basic amino acid region and a leucine zipper motif.
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==Origins of C-myc==
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Kandil and colleagues speculated that the carboxyl terminus of the c-Myc protein had a similar structure to that of the helix-loop-helix family of DNA-binding proteins. Their research showed that the <scene name='Kwon_sandbox/Hlh/1'>Helix-Loop-Helix Structure</scene> was in fact the <scene name='Kwon_sandbox/Dna_binding_domain/1'>DNA binding Domain</scene> of c-Myc and were able to establish the corresponding binding sequence as GACCACGTGGTC. This sequence was found to be present in regulatory regions of genes during replication. They compared DNA binding of c-Myc to HLH protein TFEB. They found that the two proteins had the same inner nucleotides, providing significant evidence of the homology. Kandil and colleagues then placed spacing between half-sites of the DNA binding site. The inability of c-Myc to bind to the altered site provided evidence that c-Myc dimerizes when bound to DNA.
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In 1911 a virologist named Peyton Rous saw that sarcoma in chickens could be transmitted through cell free extracts from the sarcoma tumors. This suggested that a virus was possibly the etiologic agent of the sarcoma. To see if it was true scientists studied an avian retrovirus which was found to induce myeloid leukemia, sarcomas, liver, kidney, and other tumors. They also found a gene in the body named V-myc. V-myc (myelocytomatosis viral oncogene homolog 1) is the gene in the body that aided the virus in causing cancer in the chickens. Soon after they found genes in humans with Burkitt's Lyphoma that had a similar makeup to the V-myc gene. Later they found that C-myc like V-myc causes cancer when the gene is changed or affected by something else.
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==C-myc Bonding==
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The c-myc protein cannot homodimerize without the protein Max. Max can sometimes heterodimerize with Mad family proteins. The Mad-Max, Mad3-Max, Mad4-Max, and Mnt-Max heterodimers are antagonist of c-myc. The myc-max connection is unstable which allows for high populations of dissociated monomers and it impedes reassortment dictated by the level of expression of c-myc, mad, and mxi1 genes and transduction of cell growth and differentiation signals. For oncogenic activity to occur c-myc must bind with the Max protein. All max proteins will bind to the same DNA sequence.
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==General Functions of C-myc==
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C-myc is used in cell cycle entry, proliferation, and differentiation. C-myc also helps to bind DNA which activates transcription. The c-myc lives a very short life. It is controlled by the level and temporal pattern of expression of their corresponding gene. Without C-myc an organism is unable to survive since there is nothing allowing cells to differentiate or proliferate. The organisms cannot survive after the pre-T-cell receptor proliferation is unable to be completed.
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C-myc is also involved in the body's system of remembering past diseases. T-cells help the body to remember diseases it has previously had. C-myc controls the regulation of T-cells. Without C-myc the T-cells would not be triggered to multiply when a disease that the body has seen before infiltrates the body again.
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==C-myc's Role in Cancer==
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C-myc's proliferation is induced by enhancers that help to increase immunoglobin genes functions. It has been seen that the greater amount of C-myc present the higher the chances that cancer is also present. Cancer is often able to grow best in people with weakened immune systems. Since the immune system is weak the T-cells pass over the cancer without noticing that anything is wrong. This combined with the fact that these enhancers cause C-myc to rapidly produce cells is causing cancer in a body that cannot fight it off. The newly formed cells continue to grow on each other. This causes a tumor that is cancerous that is unnoticed. The most common form of cancer that c-myc plays a role in is Burkitt's Lymphoma.
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C-myc can not be induced by enhancers unless it has translocated from its normal spot on chromosome 8 to another chromosome. When C-myc is translocated to a spot next to a gene that is an immunoglobin enhancer gene it can eventually become a tumor. The reason for this is that when these genes code for the body to make more B-cells, they inadvertantly turn on the gene adjacent to them as well. Since C-myc is now the new gene next to the enhancer gene it starts to create a lot of C-myc RNA and it then becomes C-myc transcription factor. The factor then induces cells to divide very rapidly. The cells then keep dividing until they have formed a cancerous tumor. This process shows that one cell is all that is needed to create a tumor. It has been estimated that 100,000 of the cancer related deaths per year in the United Sates are associated with changes in the C-myc gene or its expression.
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==Experiments with C-myc==
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An experiment was done to see if mice could survive embryonic development without the C-myc gene. This was done by using a mutation to make the C-myc allele null at the protein level. They gave some of the embryos one correct copy of the allele and others no correct copy. The homozygous mice (two null C-myc alleles), died between 9.5 and 10.5 days of gestation. The mice also were smaller and had many health problems. This showed that C-myc is vital to the development of embryos of organisms.
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Bahram and colleagues found that the mutation of <scene name='Kwon_sandbox/T58/1'>Thr58</scene> in c-Myc was prevalent in many cancers. They then researched the effect of Thr58 mutation and found that it was the ubiquitination site of the protein. Their in vitro experiment showed that c-Myc with Thr58 mutation had a longer turnover rate than wild type c-Myc. They also found that histadine-tagged ubiquitin octamers were unable to bind to Thr58 mutant c-Myc proteins but successfully did bind to wild type. This provided strong evidence that the site is indeed the ubiquitination site.
== References ==
== References ==
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Dang, C.V.(1999) c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism. [http://www.ncbi.nlm.nih.gov/pubmed/9858526 Molecular and Cellular Biology], 19: 1-11.
Dang, C.V.(1999) c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism. [http://www.ncbi.nlm.nih.gov/pubmed/9858526 Molecular and Cellular Biology], 19: 1-11.
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Nair & Burley (2003) X-Ray Structures of Myc-Max and Mad-Max Recognizing DNA: Molecular Bases of Regulation by Proto-Oncogenic Transcription Factors. [http://www.ncbi.nlm.nih.gov/pubmed/12553908 Cell], 112:193-205.
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Kandil, A.N. (1991) Determination of the c-MYC DNA-binding site. Proc. natl. Acad. Sci. USA Vol. 88, pp6162-6166, July 1991 Genetics
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Ohtsuki, Nishitani, Hatamochi, Yawata, & Namba (1991) Analysis of methylation in the c-Myc gene in five human myeloma cell lines. British Journal of Haematology. 77: 172-179.
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Takahashi et al., (2007) Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell. 131: 1-12.
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Kaji, Norrby, Paca, Mileikovsky, Mohseni, & Woltjen (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature. 458: 771-776.
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Gardner, Lee, & Dang (2002) The c-Myc Oncogenic Transcription Factor. [http://www.myccancergene.org/documents/MycReview.pdf]
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Dose et al., (2006) C-Myc mediates pre-TCR-induced proliferation but not developmental progression. Blood. 108: 2669-2677.
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Gilbert, S.F. http://8e.devbio.com/article.php?ch=5&id=42. September 21,2009.
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C-myc gene found to play role in immune system. The Medical News. [http://www.news-medical.net/news/2006/05/11/17924.aspx]
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Davis AC, Wims M, Spotts GD, Hann SR, Bradley A. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice.
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Bahram et al., 2000; c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover
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Genes & Development 1993 Apr;7(4):671-82
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Current revision

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Contents

Introduction

is a protein that binds to DNA and regulates transcription, a transcription factor. Bishop and collegues discovered viruses that induced chicken sarcomas. They studied the virus and identified an oncogene that would cause uncontrolled cellular proliferation. The viral oncogene that caused the sarcomas was identified as v-myc. Later on the homologous gene in chickens was discovered, and called c-myc. These findings provided evidence that activated c-Myc proteins were significant in cellular growth regulation.

Role in Cancer

Apoptosis signal pathway
Apoptosis signal pathway

c-Myc is further along in the signal transduction pathway of the epithelial growth factor receptor (EGF receptor) which deals with the proliferation of cells. Mutations of c-Myc have a strong correlation to cancer. Normally c-myc is tightly regulated and c-Myc is short lived, but cancer cells express c-myc uncontrollably and are unable to degrade the c-Myc protein. This over expression and inability to rid the protein causes it to be active much longer. thus causing the over expression of genes needed for cell proliferation causing cancer. Over expression of c-Myc is prevalent in 80% of brest cancers, 70% colorectal cancers, 90% of gynecological cancers, 50% of hepatocellular carcinomas and is particularly prevalent Burkitt’s Lymphoma.

Research of Structure and Function

c-Myc Dna complex
c-Myc Dna complex

There are two main structures of the c-Myc proteins that are significant in its function. These are the Thr58 sight and the helix-loop-helix (HLH) motif surrounded by a basic amino acid region and a leucine zipper motif.

Kandil and colleagues speculated that the carboxyl terminus of the c-Myc protein had a similar structure to that of the helix-loop-helix family of DNA-binding proteins. Their research showed that the was in fact the of c-Myc and were able to establish the corresponding binding sequence as GACCACGTGGTC. This sequence was found to be present in regulatory regions of genes during replication. They compared DNA binding of c-Myc to HLH protein TFEB. They found that the two proteins had the same inner nucleotides, providing significant evidence of the homology. Kandil and colleagues then placed spacing between half-sites of the DNA binding site. The inability of c-Myc to bind to the altered site provided evidence that c-Myc dimerizes when bound to DNA.

Bahram and colleagues found that the mutation of in c-Myc was prevalent in many cancers. They then researched the effect of Thr58 mutation and found that it was the ubiquitination site of the protein. Their in vitro experiment showed that c-Myc with Thr58 mutation had a longer turnover rate than wild type c-Myc. They also found that histadine-tagged ubiquitin octamers were unable to bind to Thr58 mutant c-Myc proteins but successfully did bind to wild type. This provided strong evidence that the site is indeed the ubiquitination site.

References

Dang, C.V.(1999) c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism. Molecular and Cellular Biology, 19: 1-11.

Kandil, A.N. (1991) Determination of the c-MYC DNA-binding site. Proc. natl. Acad. Sci. USA Vol. 88, pp6162-6166, July 1991 Genetics

Bahram et al., 2000; c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover

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Jason Kwon, Ann Taylor

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