SmokyWaters
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E
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| po
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GREAT
(E) CORRECT. The mechanism described is that of RAS oncogene activation in which the active RAS is permanently turned on and through the MAP kinase pathway activates transcription that drives cellular proliferation that leads to neoplasia.
(A) Incorrect. ADP is released from platelets to signal activation and aggregation of surrounding platelets.
(B) Incorrect. The BCR-ABL fusion gene product is the Philadelphia chromosome of chronic myelogenous leukemia that has tyrosine kinase activity.
(C) Incorrect. Cyclic AMP is not generally considered part of neoplastic processes. cAMP is a second messenger from activation of G-protein coupled cell surface receptors.
(D) Incorrect. Cyclin D appears in the mid G1 phase of the cell cycle and is part of the cell cycle machinery that is influenced by oncogenes.
(F) Incorrect. The p53 gene product is a tumor suppressor, and loss of both p53 alleles results in loss of control over cell proliferation when DNA damage occurs.
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| new_n_lost
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E MAP kinase ??
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"never argue with a fool, they'll bring you down to their level and beat you with experience" FORUM RULES-- Those who believe in telekinesis, raise my hand. I get enough exercise just by pushing my luck --P4U World.." The pure and simple truth is rarely pure and never simple."
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| new_n_lost
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ok i guess i m late
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"never argue with a fool, they'll bring you down to their level and beat you with experience" FORUM RULES-- Those who believe in telekinesis, raise my hand. I get enough exercise just by pushing my luck --P4U World.." The pure and simple truth is rarely pure and never simple."
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| SILVER
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I don't get it, what's the rush?!!
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Stop telling God how big your storm is. Instead, tell your storm how big your God is.
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| SmokyWaters
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late for?
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| genes
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hey po... thanks fr the questions. but i would lik to knw where did u read up about that map kinase, ras? thanks
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| po
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silver wrote:
I don't get it, what's the rush?!!
sorry,wanted to get neoplasia over that day.
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| po
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Review-
Three kinds of genes are targets for carcinogenic transformation:
1) proto-oncogenes promote cell growth and require the alteration of only one allele to create out of control cellular growth (dominant gene)
2) tumor suppressor genes inhibit cell growth and require the alteration of both alleles to affect cell growth (recessive oncogenes), DNA repair genes are similar
3) genes that regulate apoptosis may be dominant or recessive but influence the ability of the cell to target itself for destruction following cell damage
ONCOGENES
Proto-oncogenes are normal cellular genes that regulate cell growth, division, and differentiation. Oncogenes are cancer-causing genes derived from proto-oncogenes by mutation, retroviral transduction, gene amplification, or dislocations. Oncogenes occur as transformations of genes that normally regulate expression of growth factors and receptors, signal transducing proteins, nuclear transcriptions factors, and cyclins and their associated proteins.
Classes of Oncogenes:
Growth Factors: Genes that encode growth factors may become oncogenic. For example, cells that produce PDGF may also develop receptors for it and become permanently turned on via autocrine stimulation. Usually, the PDGF gene (sis) is normal, but oncogenes such as ras cause PDGF to be overexpressed.Excess growth factor itself cannot completely transform a cell, but in conditions of excessive growth and cell division, other mutations become more likely.
Growth Factor Receptors: most are transmembrane proteins that cause phosphorylation of proteins on the cytoplasmic side when activated. Normally, the cytoplasmic side gets transiently turned "on" and then rapidly deactivated. Oncogenic receptors exist in a prolonged "on" state, even in the absence of bound growthfactor. Point mutations in the ret protooncogene (codes for receptor associated with glial cells) are associated with MEN and familial medullary thyroid carcinoma.Growth factor receptors may also be overexpressed. c-erb1 codes for an EGF receptor overexpressed in many squamous cell cas, and c-erb 2 in the adenocas of the breast, ovary, lung and others.
Signal Transducing Proteins: these proteins exist on the inner plasma membrane and following activation work to phosphorylate cytoplasmic proteins. Ras, a GTP cleaving protein receptor associated transducing protein, is the prototype and mutated versions of the ras proteins are present in 10-20% of human cancers.
The normal GTPase activity of ras protein is accelerated when in association with GAPs (GTPase-activating proteins). Ras normally works to activate MAP (mitogen activated protein) kinase that increase nuclear transcription factors. Mutated forms of ras bind GAP normally, but the GTPase activity of GAP fails to occur.
Translocation of the signal transducing protein (non-receptor associated) c-abl on chromosome 9 to the bcr region of chromosome 22 activates it to increase cell growth. This translocation is associated with CML.
Nuclear Transcription Proteins: these proteins influence DNA synthesis in the nucleus. C-myc, forms a heterodimer with max protein, and the myc-max combination activates transcription. Mad, a similar protein to myc, may also combine with max to turn off transcription and is therefore a tumor-suppressor gene.
Cyclins and CDKs: CDKs are present within the cell at all times and help the cell through the cell cycle. Cyclins are synthesized and then rapidly degraded and work to activate the CDKs. CDKIs regulate the activity of CDKs. CDK4 mutation seems to be implicated in melanomas and other cancers.
Methods of Activation of Oncogenes:
1. Point mutations: typical ofras proteins
2. Chromosomal rearrangements: translocation may associate a growth factor or receptor with an actively transcribed area, or result in the formation of an active hybrid protein. EX: philly chromosome c-abl-bcr has hybrid activity
3. Gene Amplification: duplication, multiplication of DNA sequences in the genome. Associated with N-myc in neuroblastoma and c-erb 2 in breast ca.
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| po
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Tumor Suppressor Genes
Tumor suppressor genes are normal cell genes that "brake" cell division and cycling at various point in the cell cycle. They work through similar mechanisms to proto-oncogenes, through signal transduction, through cell surface receptors and nuclear transcription regulators.
Suppressor genes are "recessive" and require loss of both copies of the normal before cancer becomes likely, the "two-hit" model of carcinogenesis.
Retinoblastoma models this behavior and exists as 60% sporadic and 40% familial, but occurs much earlier if familial. The theory is that both alleles of Rb must be ineffective before tumor suppression is lost. In the familial forms, all somatic cells have inherited one defective allele, and only one cell must lose its other allele to become predisposed to produce tumors. pRb works to prevent cells in G1 from advancing to S phase. This is an extremely sensitive transition since no further growth factors are required to complete mitosis following progression into S phase. pRb normally exists in an active,
hypophosphorylated state and when phosphorylated, it releases the brakes and allows cell division to progress. Most likely, Rb forms tumors in the retina and osteosarcoma because deletion of both active alleles should trigger apoptosis. But, for reasons not fully understood, retinoblasts fail to die following transformation.
p53, a protein exclusive to the nucleus, is the most common transformed gene in human cancer, presenting in over 50% of human tumors. p53, designated "guardian of the genome," acts in the nucleus to stop replication of damaged cells. Following damage, p53 gets rapidly up regulated and its accumulation triggers increased transcription of DNA repair proteins and those that stop the cell cycle. If repair occurs, the cell cycle resumes. If not, p53 plays a role in triggering apoptosis. Loss of both normal alleles of p53 causes the cell cycle to continue with the mistakes in DNA transcription intact.
p73 has recently been discovered and appears to work by similar mechanisms.
Other tumor suppressor genes include NF-1, NF-2, VHL, and WT-1.
Suppressors of apoptosis involved in ca include bcl-2 , which inhibits apoptosis and is transformed in most B cell lymphomas. Growth arises from decreased cell death rather than increased cell proliferation. The bax and bad gene accelerates cell death and opposes bcl-2.
Defective DNA repair genes are implicated in the development of cancers as they may allow cell division despite mutated DNA. HNPCC (hereditary nonpolyposis colon cancer) illustrates a cancer associated with defects in DNA repair. These genes are not considered oncogenic but favor conditions that allow mutations in normal oncogenes. XP also arises from defects in DNA repair genes.
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| SmokyWaters
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NICEEEee...
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