Understand what medical/biological methods are used to identify tumors Understan
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Understand what medical/biological methods are used to identify tumors Understand how cancer cells differ from normal cells, and how cancer cells can be grown in vitro and in vivo Understand the various ways that the DNA sequence can be mutated-from the chromosomal level to the base sequence level Understand how physical and chemical carcinogens mutate the DNA; what kinds of adducts are produced and how they modify DNA nucleotides or basepairing Understand how DNA Polymerase 'deals with' mutated nucleotides during DNA synthesis; how the different DNA Damage Repair mechanisms correct mutations, and what kinds of mutations the different repair mechanisms can or cannot correct. Be able to define the differences between oncogenes and tumor suppressor genes in terms of what kinds of mutations produce them; what the normal functions of these kinds of genes are, and how mutations alter these functions to promote tumorigenesis Define the different types of protein motifs/functional areas that determine transcription factor activity Be able to describe the composition and function of the AP-1 transcription factor, and how mutation:s in either Jun or Fos type proteins alter the function of AP-1 work to promote tumorigenesis Understand epigenetic modifications and how they promote tumorigenesis the differences between HATs and HDACs; how they alter histones, and how this affects gene expression how DNA methylations occur and how they affect gene expression how miRNAs work'; what is an oncmiR? A tsmiR? How do they function in cancer? Understand the structures of the 4 EGFR Family member receptors, how they bind ligand, how they interact with each other Understand the concept of a RTK, transphosphorylation, SH2-domain protein binding subsequent binding of other adapter proteins (Grb2, etc), activation of Ras, GEFs and GAPs Understand downstream signaling from EGFR: MEK/ERK promoting proliferation, PI3K/AKT promoting cell survival; how are these dysregulated in cancer? What is the role of PTEN deletion in tumorigenesis? Ras mutation? Raf mutation? How were oncogenes discovered? What is Src? How is Src mutated to confer oncogenic activity? How are other oncogenes activated? Throughout the lectures: what THERAPEUTICS are in use or being tested to cancer? What are their targets and mechanisms of action?Explanation / Answer
Tumor markers are the substances that are secreted by the cancer cells or the other cells of the body in response to cancer. These markers are used in diagnosis of the cancer in the body. Many markers are also secreted by normal cells as well as the cancer cells but in cancer tissues the amount of markers get increased. These substances are present in the blood, urine, body fluids and in the tissues. Nowadays change in pattern of Gene expression can also be used for diagnostics. Measurements of tumor markers are also combined with some other diagnostic methods like biopsies.
Example : ALK gene function is used as a marker for Non small cell lung cancer, Alpha-fetoprotein use as a marker for liver and germ cell cancers, CA-125 for ovarian cancer.
b) Difference between cancer and normal cells
Carcinogens are the molecules that leads to cancer and these carcinogens can be classified as physical (X- ray radiation causes DNA breakage and non ionizing radiation Ultraviolet light pyrimidine dimers formation specially between Thymine and Thymine) , Chemicals ( Acrylamide, nitrosamines and polycyclic hydrocarbons produced by the tobacco smoke) and Viruses ( Human papilloma virus and epstein bars viruses).
Chemical carcinigens can cause Base modifications which leads to change in the pairing potentials of the standard watson and crick base pairing like Adenine amino form converted to imino form so adenine starts pairing with Cytosine instead with thymine leads to transition and transversion point mutations.
Genes can be classified as oncogenes, these are the normal proto-oncogenes that plays role in the cell division , apoptois, cell motility etc like Cyclin D1 , Raf-1, Bcl-2 , amplification of the EGFR receptors mutation etc and Tumorsuppressor genes which suppreses the growth of tumor like p53 protein and Rb1 ,acts as a Gate keeper proteins so that none of the cells having DNA mutation can undergo cell division, first it leads to the activation of repair enzymes so that DNA get repaired if the DNA get not repaired then cell undergo apoptosis.
Chromosomal aberrations that causes mutation and changes of oncogene gene expressions are deletion, duplication, amplification, inversion and translocations.
Gain of function mutation occurs in the oncogenes that causes the overexpression of the proto-oncogenes like CyclinD1 overexpression leads to uncontrollable cell growth and loss of function mutation occurs in the tumor suppressor proteins downregulation of tumor suppressor genes.
Motifs : Transcriptions factors contain combinations of alpha helix and beta pleated sheet secondary structure. These patterns are called supersecondary structure called motifs. Various motifs are present in the transcription factors like motif , -meander pattern and motifs.
AP-1 transcription factors regulate number of processes like differentiation, proliferation and apotosis in response to various stimuli like cytokines. AP-1 is a hetrodimer composed of c-Fos and c-Jun. Sumoylation of c-Fos and c-Jun lowers AP-1 transactivation activity.
Epigenetic modifications, or “tags,” such as DNA methylation and histone modification can alter the gene expression. Modifications like methylation in the DNA and acetylation in the histones can leads downregulation of the gene and upregulation of the gene expression respectively.
Chromatin is consist of DNA and proteins and for transcription of genes to occur various histone modifications occurs like acetylation by HATs (Histone transacetylases) which imparts negative charge to histone and causes the repulsion between the DNA which already has negative charge due to the presence of phosphate groups in DNA and Histones having acetyl groups. So, it allows RNA polymerases to bind at the promoter regions of the gene and causes upregulation of gene expression. Acetylation in the oncogenes leads overexpression of proto oncogenes.
Methylation in the DNA sequence leads to downregulation of the tumor suppressor genes expression so it's suppressive function gets downregulated.
miRNAs are the endogenous non coding RNAs that causes the gene silencing by binding with the target mRNA and causes its degradation. Deletion of some miRNAs that regulates the expression of cyclinD1 gene found to be deleted in the cancer cells which causes increase proliferation.
PI3k pathway is found to be the most activated and deregulated pathway in the cancer cells. This pathways controls many functions of the cells like proliferation, apoptosis etc.
In the literature mutations found in the PI3K and AKT components of pathway leads to overactivation of the pathway.
Expression of pTEN (phosphotensin deleted on chromosome 10) protein found to be downregulated in the cancer cells.
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