Cancer Causation and Development

7/30/2019 Cancer Causation and Development

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Cancer Causation and

Development

Udadi Sadhana


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CANCER CAUSATIONA wide diversity of biological, chemical, and physical agentshave the potential for inducing cancer in man. However, the

majority of man's common cancers have no recognized cause(breast and ovary in females, prostate in males, brain andpancreas in both sexes). Many of these spontaneously-developing cancers may result from the effects of endogenousmutagens, i.e. mutagens that originate in the body, such asoxygen free radical.

Each of the various classes of agents known to induce cancerin man or animal (naturally or experimentally differ; each has adifferent mechanism of action, and the epidemiology andpathogenesis of the disease processes also differ. Thus, ananalysis of each of the individual causes of cancer is aperplexing, complicated undertaking. Since in this course little

time is available to explore these issues in detail and discussexamples individually, we are obliged to provide yougeneralization annotated by specific examples.


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An enormous body of data accumulated from observations inhumans and experiments in animals indicate that host factors are

critical to the development of cancer. These involve a wide variety ofgenetic influences as well as factors unique to the environment andlifestyle of the host. All of us experience DNA injury on a continuousbasis in both our somatic and reproductive cells. Fortunately, thisinjury is usually repaired by natural mechanisms. When it is not, amutation occurs. The mutation may be silent, it may be lethal, it

could cause a developmental abnormality, or it could result incancer. Usually, however, several mutational changes mustaccumulate in the cell genome for cancer to develop.

Factors related to host susceptibility may determine whether or notdisease develops. One can look at this possibility optimistically orpessimistically. From a pessimistic perspective, the notion that weall experience DNA changes which could result in clinical cancer isfrightening. From an optimistic perspective, we can accept the factthat cancer occurs uncommonly, whereas DNA damage is aneveryday event.


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CANCER DEVELOPMENTCancer develops when critical changes in the DNA of cells results in their

loss of responsitivity to nornal cellular control mechanisms.

1. DNA Changes Occurring in Humans Associated with Cancer

Addition of "new" DNA acquired and integrated with host DNA. Examples: Epstein-Barr Virus (EB

Oxidative injury to DNA

Examples: Ionizing irradiation (clinical radiation, weapons, and energygeneration)- leukemia, breast, thyroid, bronchogenic carcinoma

Adducts to DNA with secondary effects on DNA structure and makeup Examples: Metabolism of polycyclic aromatic hydrocarbons results in the

generation of electrophils which adduct to DNA in bronchial mucosa cells ofcigarette smokers- lung cancer Metabolism of aflatoxin- food contaminants andadditives - stomach and liver cancer

Induction of chromosomal gaps, breaks, translocations, and sister

chromatid exchanges can result in the loss of "key" genetic informationresulting in disorganized function.

The loss of SUPPRESSOR genes from cells by these mechanisms may beone of the key factors allowing cancer to develop and progress.


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2. Radiation

Types: Ionizing irradiation

X ray

alpha, beta, gamma particles neutrons

radon gas - alpha particle emitter

Non-ionizing

UV light


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3.Electromagnetic Force

A complex topic of contemporary interest but nocause and effect relation to cancer has beenestablished

4. Variables Affecting Outcome

Dosage effects

Type of irradiation- i.e., alpha, beta, etc.

Acute exposure (one time) vs. chronic exposure Age susceptibility factors


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5. Chemicals

Direct Acting: Heavy metals - arsenic, nickel, chromium Polycyclic aromatic hydrocarbons

Nitrosamines

Chemotherapeutic agents

Indirect Acting: Hormones- such as estrogen and estrogenic compounds such as

polychlorobyphenyls (PCB) and Agent Orange (dioxins) Promoters- many constituents of cigarette smoke are promoter

substances. A promoter is not a carcinogen, but acts to enhancethe effects of a initiator carcinogen by increasing the likelihoodthat cancer will develop or shorten the latency period.

Many common chemicals are carcinogenic in animals, but

relatively few have been proven to cause cancer in humans. Dosage effects- threshold considerations


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6. Viruses

DNA- Papillomaviruses, genital papillomas (condylomas) and

carcinoma of cervix Hepatitis B virus - hepatoma

Epstein-Barr Virus

RNA- HTLV-1, the agent causing T Cell Leukemia/lymphoma

7. Physical Agents

Asbestos- Mesothelioma- a rare pleura cancer

Schistosoma hematobium (a common parasite in Africa thatlays eggs in the bladder wall)- resulting in urinary bladder

cancer


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CHEMICAL CARCINOGENESISThe concept of chemical carcinogenesis was first introduced to medical science

during the industrial revolution. In that era, residential and industrial building heatingwas primarily provided by coal fires.

Sir Percival Potts, a surgeon, noted that many of these young men developed "warts"on the scrotum and later warts of this type sometimes became invasive cancers. Heassociated their work with the development of the "warts" and concluded that the sootin the chimneys was responsible. Innovatively, Potts, provided an opportunity forthese youngsters to bath routinely so that the soot would not accumulate in the

corrugated skin of the scrotum.

We know now that coal soot contains coal tar that is comprised of a large number ofcomplex hydrocarbons including the polycyclic aromatic hydrocarbons. The basicprecursor chemicals are found in coal, wood and petroleum where there are notcarcinogenetic, but after incineration at elevated temperatures the noncarcinogenetic

chemical are converted to carcinogens, i.e., they are active carcinogens uponmetabolism in epithelial cells on the surfaces of the respiratory tract. Humankind noware exposed to these polycyclic aromatic hydrocarbons in PETROLEUMPRODUCTS, COAL EFFLUENTS such as those from coke ovens, and cigarettesmoke.


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Everyone knows that cigarettes are the major cause ofbronchogenic carcinoma (lung cancer). The mechanisms are clearly

outlined in your book. You should have in mind a very specificknowledge as to how the polycyclic aromatic hydrocarbons incigarette smoke are transformed to electrophils by CYTOCHROMEP450 MONOOXYGENASE, the ELECTROPHILS then have theability to form adducts on the DNA and ultimately to cause DNAdamage. This is discussed in your text. I will discuss smoking anddisease in the Environmental Pathology lecture.

Bronchogenic carcinoma is an example of MULTISTAGECARCINOGENESIS in which multiple cumulative chemical injuriesto the cells of the respiratory tract ultimately result in cancer. Itintroduces the concept of the initiator and the promoter of cancer. Inthis concept, the polycyclic aromatic hydrocarbons are the initiator of

DNA injury but many additional chemicals in the cigarette smokestimulate cell proliferation and increase sensitivity to thecarcinogenic initiator.


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VIRAL CARCINOGENESISLEUKEMIA AND LYMPHOMAS occur in approximately 1% of the general

population. As noted above, the prevalence of these diseases is increased inindividuals exposed to excessive concentrations of irradiation (atomic bombvictims) and certain chemicals, including chemotherapeutic agents used totreat solid tumors such as Hodgkin's disease.

The role ofRETROVIRUSESin human leukemia has become apparent in recentyears with the appearance ofHTLV-1,the cause of T-CELL LEUKEMIA.

Burkitt's lymphoma is a unique malignancy of children, which is prevalent inthe highlands of East Africa. It comprises about 1% of the lymphomasoccurring in children in this country and the rest of the western world today.The tumor biology is intimately related to infections withEPSTEIN-BARR (EB)virus, a member of the Herpesvirus group. In East Africa, youngsters almostinvariably develop the disease before the age of 10. They exhibit massivetumors having a unique morphology, particularly in the mandible of the face,

and in females in the ovaries. These are unusual locations for lymphomas inchildren.

Herpesvirusesof other types have been shown to play a role in carcinogenesis.Herpesvirus type II was thought to play a role in carcinoma of the cervix.


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FOREIGN BODY CARCINOGENESIS Mesothelioma

In 1960, an inquisitive pathologist and epidemiologist discovered thatasbestos, of the amphibole type, is associated with malignant mesotheliomas,an exceedingly rare form of tumor of the pleura. Since that time, countlessAmericans have developed mesotheliomas and died as a consequence ofasbestos exposure. These unique tumors spread in the pleural cavity of thelung of individuals and expand to encroach upon the lung until the individualsuffocates. Rarely they metastasize. Occasionally, malignant mesotheliomasoccur in the abdominal cavity. The mechanisms whereby asbestos causes

mesothelioma remains to be defined.

Bladder Cancer

Schistosoma hematobiumis an exceedingly common parasitic infestation ofthe venules of the urinary bladder in individuals residing in certain parts ofAfrica and Asia. As a result, the eggs are deposited in the walls of the urinarybladder where they fester and cause a granulomatous response. This irritatesthe mucosa of the bladder resulting in a hyperplasia of the transitional

epithelium of the bladder. Occasionally it becomes malignant, resulting insquamous cell carcinoma. There is a strong association of cigarette smokingwith urinary tract carcinomas in those who live in the western world. Inendemic areas of Schistosomiasis, there may also be the superimposed effectof a chemical carcinogen which is excreted through the urine. We just don'tknow.


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Tumor suppressor gene

A tumor suppressor gene is a gene that

reduces the probability that a cell in a

multicellular organism will turn into a tumorcell. A mutation ordeletion of such a gene

will increase the probability of the

formation of a tumor.
http://en.wikipedia.org/wiki/Genehttp://en.wikipedia.org/wiki/Cell_%28biology%29http://en.wikipedia.org/wiki/Multicellular_organismhttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Mutationhttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Mutationhttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Multicellular_organismhttp://en.wikipedia.org/wiki/Cell_%28biology%29http://en.wikipedia.org/wiki/Gene


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Two-hit hypothesis

Unlike oncogenes, tumor suppressor genes

generally follow the 'two-hit hypothesis,' which

implies that both alleles that code for a particular

gene must be affected before an effect ismanifested. This is due to the fact that if only

one allele for the gene is damaged, the second

can still produce the correct protein. In other

words, tumor suppressors are usually nothaploinsufficient, although there are notable

exceptions (the p53 gene product).
http://en.wikipedia.org/wiki/Oncogeneshttp://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/Haploinsufficienthttp://en.wikipedia.org/wiki/P53http://en.wikipedia.org/wiki/P53http://en.wikipedia.org/wiki/Haploinsufficienthttp://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/Oncogenes


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FunctionsTumor suppressor genes, or more precisely, the proteins for whichthey code, either have a dampening or repressive effect on the

regulation of the cell cycle or promote apoptosis, and sometimes doboth. The functions of tumor suppressor proteins fall into severalcategories including the following:

Repression of genes that are essential for the continuingof the cellcycle. If these genes are not expressed, the cell cycle will not

continue, effectively inhibiting cell division. Coupling the cell cycle to DNA damage. As long as there is

damaged DNA in the cell, it should not divide. If the damage can berepaired, the cell cycle can continue.

If the damage can notbe repaired, the cell should initiate apoptosis,or programmed cell death, to remove the threat it poses for the

greater good of the organism. Some proteins involved in cell adhesion prevent tumor cells from

dispersing, block loss ofcontact inhibition, and inhibit metastasis.
http://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Code_forhttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Gene_repressionhttp://en.wikipedia.org/wiki/Protein_expressionhttp://en.wikipedia.org/wiki/Cell_divisionhttp://en.wikipedia.org/wiki/DNA_damagehttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Contact_inhibitionhttp://en.wikipedia.org/wiki/Metastasishttp://en.wikipedia.org/wiki/Metastasishttp://en.wikipedia.org/wiki/Contact_inhibitionhttp://en.wikipedia.org/wiki/Cell_adhesionhttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/DNA_damagehttp://en.wikipedia.org/wiki/Cell_divisionhttp://en.wikipedia.org/wiki/Protein_expressionhttp://en.wikipedia.org/wiki/Gene_repressionhttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Code_forhttp://en.wikipedia.org/wiki/Protein


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Examples

The first tumor suppressor protein

discovered was thepRb protein in human

retinoblastoma; however, recent evidence

has also implicated pRb as a tumorsurvival factor.

Another important tumor suppressor is the

p53 tumor suppressor protein produced bythe TP53 gene.
http://en.wikipedia.org/wiki/PRb_proteinhttp://en.wikipedia.org/wiki/Humanhttp://en.wikipedia.org/wiki/Retinoblastomahttp://en.wikipedia.org/wiki/P53http://en.wikipedia.org/wiki/TP53http://en.wikipedia.org/wiki/TP53http://en.wikipedia.org/wiki/P53http://en.wikipedia.org/wiki/Retinoblastomahttp://en.wikipedia.org/wiki/Humanhttp://en.wikipedia.org/wiki/PRb_protein


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p53

p53, also known as protein 53 (TP53), is a transcription factorthatregulates the cell cycle and hence functions as a tumor suppressor.It is important in multicellular organisms as it helps to suppresscancer. p53 has been described as "the guardian of the genome","the guardian angel gene", or the "master watchman", referring to itsrole in conserving stability by preventing genome mutation.

The name p53 is in reference to its apparent molecular mass: it runsas a 53 kilodalton (kDa) protein on SDS-PAGE. Its theoreticalmolecular mass, based on the sum of its amino acid residues, is infact only 43.7 kilodalton. This difference is due to the high number ofamino-acid proline in the p53 protein. This leads to an aberrant

migration on SDS-PAGE. This observation is also found for p53from other species, such as rodents, frogs, and fish.
http://en.wikipedia.org/wiki/TP53http://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Tumor_suppressor_genehttp://en.wikipedia.org/wiki/Multicellular_organismhttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Molecular_masshttp://en.wikipedia.org/wiki/Kilodaltonhttp://en.wikipedia.org/wiki/SDS-PAGEhttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Prolinehttp://en.wikipedia.org/wiki/SDS-PAGEhttp://en.wikipedia.org/wiki/SDS-PAGEhttp://en.wikipedia.org/wiki/SDS-PAGEhttp://en.wikipedia.org/wiki/SDS-PAGEhttp://en.wikipedia.org/wiki/Prolinehttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/SDS-PAGEhttp://en.wikipedia.org/wiki/SDS-PAGEhttp://en.wikipedia.org/wiki/SDS-PAGEhttp://en.wikipedia.org/wiki/Kilodaltonhttp://en.wikipedia.org/wiki/Molecular_masshttp://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Multicellular_organismhttp://en.wikipedia.org/wiki/Tumor_suppressor_genehttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/TP53


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p53 (blue) bound to a short DNA

fragment (orange); zinc ions (green).Based on PDB id 1TUP.

tumor protein p53
http://en.wikipedia.org/wiki/Image:P53.png


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p53 has many anti-cancer mechanisms:

It can activate DNA repairproteins when DNA hassustained damage.

It can also hold the cell cycle at the G1/S regulation

point on DNA damage recognition (if it holds the cellhere for long enough, the DNA repair proteins will havetime to fix the damage and the cell will be allowed tocontinue the cell cycle.)

It can initiate apoptosis, the programmed cell death, ifthe DNA damage proves to be irreparable.
http://en.wikipedia.org/wiki/DNA_repairhttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/DNA_repair


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p53 pathway:In a normal cellp53 is inactivated by its negative

regulator, mdm2. Upon DNA

damage or other stress, various

pathways will lead to the

dissociation of the p53 and mdm2

complex. Once activated, p53 willeither induce a cell cycle arrest to

allow repair and survival of the

cell or apoptosis to discard the

damage cell. How p53 make this

choice is currently unknown.
http://en.wikipedia.org/wiki/Image:P53_pathways.jpg


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Regulation of p53 activity p53 becomes activated in response to a myriad of stress types, which include but is not limited to

DNA damage (induced by eitherUV, IR or chemical agents,such as hydrogen peroxide), oxidativestress, osmotic shock, ribonucleotide depletion and deregulated oncogene expression. This

activation is marked by two major events. Firstly, the half-life of the p53 protein is increaseddrastically, leading to a quick accumulation of p53 in stressed cells. Secondly, a conformationalchange forces p53 to take on an active role as a transcription regulatorin these cells. The criticalevent leading to the activation of p53 is the phosphorylation of its N-Terminal domain. The N-Terminal transcriptional activation domain contains a large number of phosphorylation sites andcan be considered as the primary target for protein kinases transducing stress signals.

The protein kinases which are known to target this transcriptional activation domain of p53, canroughly be divided into two groups. A first group of protein kinases belongs to the MAPK family

(JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such asmembrane damage, oxidative stress, osmotic shock, heat shock, etc... A second group of proteinkinases (ATR, ATM, Chk1, Chk2, DNA-PK, CAK) is implicated in the genome integrity checkpoint,a molecular cascade that detects and responds to several forms of DNA damage caused bygenotoxic stress.

In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A proteincalled Mdm2 binds to p53 and transports it from the nucleus to the cytosol where it becomesdegraded by the proteasome. Phosphorylation of the N-terminal end of p53 by the above

mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are thenrecruited to p53 and induce a conformational change in p53 which prevents Mdm2-binding evenmore. Trancriptional coactivators, like p300 orPCAF, then acetylate the carboxy-terminal end ofp53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes.
http://en.wikipedia.org/wiki/DNA_damagehttp://en.wikipedia.org/wiki/UVhttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Oxidative_stresshttp://en.wikipedia.org/wiki/DNA_damagehttp://en.wikipedia.org/wiki/UVhttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Oxidative_stresshttp://en.wikipedia.org/wiki/Oxidative_stresshttp://en.wikipedia.org/wiki/Osmotic_shockhttp://en.wikipedia.org/wiki/Conformational_changehttp://en.wikipedia.org/wiki/Conformational_changehttp://en.wikipedia.org/wiki/Transcriptional_regulationhttp://en.wikipedia.org/wiki/Protein_kinaseshttp://en.wikipedia.org/wiki/MAPKhttp://en.wikipedia.org/wiki/MAPKhttp://en.wikipedia.org/wiki/Mdm2http://en.wikipedia.org/wiki/Cell_nucleushttp://en.wikipedia.org/wiki/Cytosolhttp://en.wikipedia.org/wiki/Proteasomehttp://en.wikipedia.org/wiki/P300/CBPhttp://en.wikipedia.org/wiki/PCAFhttp://en.wikipedia.org/wiki/P300/CBPhttp://en.wikipedia.org/wiki/PCAFhttp://en.wikipedia.org/wiki/PCAFhttp://en.wikipedia.org/wiki/P300/CBPhttp://en.wikipedia.org/wiki/Proteasomehttp://en.wikipedia.org/wiki/Cytosolhttp://en.wikipedia.org/wiki/Cell_nucleushttp://en.wikipedia.org/wiki/Mdm2http://en.wikipedia.org/wiki/MAPKhttp://en.wikipedia.org/wiki/Protein_kinaseshttp://en.wikipedia.org/wiki/Transcriptional_regulationhttp://en.wikipedia.org/wiki/Conformational_changehttp://en.wikipedia.org/wiki/Conformational_changehttp://en.wikipedia.org/wiki/Osmotic_shockhttp://en.wikipedia.org/wiki/Oxidative_stresshttp://en.wikipedia.org/wiki/Oxidative_stresshttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/UVhttp://en.wikipedia.org/wiki/DNA_damage


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Role in disease If the TP53 gene is damaged, tumor suppression is severely reduced. People who

inherit only one functional copy of the TP53 gene will most likely develop tumors in

early adulthood, a disease known as Li-Fraumeni syndrome. The TP53 gene can alsobe damaged in cells by mutagens (chemicals, radiation orviruses), increasing thelikelihood that the cell will begin uncontrolled division. More than 50 percent ofhumantumors contain a mutation ordeletion of the TP53 gene. Increasing the amount ofp53, which may initially seem a good way to treat tumors or prevent them fromspreading, is in actuality not a usable method of treatment, since it can causepremature aging.[citation needed] However, restoring endogenous p53 function holdsa lot of promise.

Certain pathogens can also affect the p53 protein that the TP53 gene expresses.One such example, the Human papillomavirus (HPV), encodes for a protein, E6,which binds the p53 protein and inactivates it. This, in synergy with the inactivation ofanother cell cycle regulator, p105RB, allows for repeated cell division manifestestedin the clinical disease ofwarts.

In healthy humans, the p53 protein is continually produced and degraded in the cell.The degradation of the p53 protein is, as mentioned, associated with MDM2 binding.In a negative feedback loop MDM2 is itself induced by the p53 protein. Howevermutant p53 proteins often don't induce MDM2, and are thus able to accumulate atvery high concentrations. Worse, mutant p53 protein itself can inhibit normal p53protein levels.
http://en.wikipedia.org/wiki/Li-Fraumeni_syndromehttp://en.wikipedia.org/wiki/Mutagenhttp://en.wikipedia.org/wiki/Chemical_substancehttp://en.wikipedia.org/wiki/Radiationhttp://en.wikipedia.org/wiki/Virushttp://en.wikipedia.org/wiki/Humanhttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Mutationhttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Wikipedia:Citing_sourceshttp://en.wikipedia.org/wiki/Human_papillomavirushttp://en.wikipedia.org/wiki/E6_-_proteinhttp://en.wikipedia.org/w/index.php?title=P105RB&action=edithttp://en.wikipedia.org/wiki/Warthttp://en.wikipedia.org/wiki/Warthttp://en.wikipedia.org/w/index.php?title=P105RB&action=edithttp://en.wikipedia.org/wiki/E6_-_proteinhttp://en.wikipedia.org/wiki/Human_papillomavirushttp://en.wikipedia.org/wiki/Wikipedia:Citing_sourceshttp://en.wikipedia.org/wiki/Genetic_deletionhttp://en.wikipedia.org/wiki/Mutationhttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Humanhttp://en.wikipedia.org/wiki/Virushttp://en.wikipedia.org/wiki/Radiationhttp://en.wikipedia.org/wiki/Chemical_substancehttp://en.wikipedia.org/wiki/Mutagenhttp://en.wikipedia.org/wiki/Li-Fraumeni_syndromehttp://en.wikipedia.org/wiki/Li-Fraumeni_syndromehttp://en.wikipedia.org/wiki/Li-Fraumeni_syndrome


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History

p53 was identified in 1979 byArnold Levine, David Lane, and Lloyd Old,working at Princeton University, Imperial Cancer Research Fund (UK), andSloan-Kettering Memorial Hospital, respectively. It had been hypothesizedto exist before as the target of the SV40 virus, a strain that induceddevelopment of tumors. The TP53 gene from the mouse was first cloned byPeter Chumakov of the Moscow Academy of Sciences in 1982, andindependently in 1983 by Moshe Oren (Weizmann Institute).

It was initially presumed to be an oncogene due to the use of mutated cDNAfollowing purification of tumour cell mRNA. Its character as a tumorsuppressor gene was finally revealed in 1989 by Bert Vogelstein working atJohns Hopkins School of Medicine.

Warren Maltzman, of the Waksman Institute of Rutgers University firstdemonstrated that TP53 was responsive to DNA damage in the form of

ultraviolet radiation. In a series of publications in 1991-92, Michael Kastan,Johns Hopkins University, reported that TP53 was a critical part of a signaltransduction pathway that helped cells respond to DNA damage.

In 1993, p53 was voted molecule of the yearby Science magazine.
http://en.wikipedia.org/wiki/1979http://en.wikipedia.org/w/index.php?title=Arnold_Levine&action=edithttp://en.wikipedia.org/wiki/David_Lane_(Oncology)http://en.wikipedia.org/w/index.php?title=Lloyd_Old&action=edithttp://en.wikipedia.org/wiki/Princeton_Universityhttp://en.wikipedia.org/wiki/Imperial_Cancer_Research_Fundhttp://en.wikipedia.org/wiki/Sloan-Kettering_Memorial_Hospitalhttp://en.wikipedia.org/wiki/SV40http://en.wikipedia.org/wiki/SV40http://en.wikipedia.org/wiki/TP53http://en.wikipedia.org/w/index.php?title=Peter_Chumakov&action=edithttp://en.wikipedia.org/w/index.php?title=Moscow_Academy_of_Sciences&action=edithttp://en.wikipedia.org/w/index.php?title=Moshe_Oren&action=edithttp://en.wikipedia.org/wiki/Weizmann_Institutehttp://en.wikipedia.org/wiki/Oncogenehttp://en.wikipedia.org/wiki/CDNAhttp://en.wikipedia.org/wiki/MRNAhttp://en.wikipedia.org/wiki/Tumor_suppressor_genehttp://en.wikipedia.org/wiki/Tumor_suppressor_genehttp://en.wikipedia.org/wiki/1989http://en.wikipedia.org/wiki/Bert_Vogelsteinhttp://en.wikipedia.org/wiki/Johns_Hopkins_School_of_Medicinehttp://en.wikipedia.org/wiki/1993http://en.wikipedia.org/wiki/Science_(journal)http://en.wikipedia.org/wiki/Science_(journal)http://en.wikipedia.org/wiki/1993http://en.wikipedia.org/wiki/Johns_Hopkins_School_of_Medicinehttp://en.wikipedia.org/wiki/Bert_Vogelsteinhttp://en.wikipedia.org/wiki/1989http://en.wikipedia.org/wiki/Tumor_suppressor_genehttp://en.wikipedia.org/wiki/Tumor_suppressor_genehttp://en.wikipedia.org/wiki/MRNAhttp://en.wikipedia.org/wiki/CDNAhttp://en.wikipedia.org/wiki/Oncogenehttp://en.wikipedia.org/wiki/Weizmann_Institutehttp://en.wikipedia.org/w/index.php?title=Moshe_Oren&action=edithttp://en.wikipedia.org/w/index.php?title=Moscow_Academy_of_Sciences&action=edithttp://en.wikipedia.org/w/index.php?title=Peter_Chumakov&action=edithttp://en.wikipedia.org/wiki/TP53http://en.wikipedia.org/wiki/SV40http://en.wikipedia.org/wiki/Sloan-Kettering_Memorial_Hospitalhttp://en.wikipedia.org/wiki/Sloan-Kettering_Memorial_Hospitalhttp://en.wikipedia.org/wiki/Sloan-Kettering_Memorial_Hospitalhttp://en.wikipedia.org/wiki/Imperial_Cancer_Research_Fundhttp://en.wikipedia.org/wiki/Princeton_Universityhttp://en.wikipedia.org/w/index.php?title=Lloyd_Old&action=edithttp://en.wikipedia.org/wiki/David_Lane_(Oncology)http://en.wikipedia.org/w/index.php?title=Arnold_Levine&action=edithttp://en.wikipedia.org/wiki/1979


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Retinoblastoma protein

The retinoblastoma protein, also called pRb orRb, is a tumor

suppressorprotein found to be dysfunctional in a number of types ofcancer. pRb was so named because retinoblastoma cancer resultswhen the protein is inactivated by a mutation in both alleles of theRB1 gene that codes forit. The "p" in pRb stands for protein and is away to distinguish it from the gene, Rb. pRb is usually present as aphosphoprotein inside cells and is a target forphosphorylation byseveral kinases as described below. One highly studied function of

pRb is to prevent the cell from dividing or progressing through thecell cycle. Thus, when pRb is ineffective at this role, mutated cellscan continue to divide and may become cancerous.

pRb is a member of the 'Pocket protein family', because it has apocket to which proteins can bind. Oncogenic proteins such as

those produced by cells infected by high-risk types ofhumanpapillomaviruses can bind and inactivate pRb, which can lead tocancer.
http://en.wikipedia.org/wiki/Tumor_suppressor_genehttp://en.wikipedia.org/wiki/Tumor_suppressor_genehttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Retinoblastomahttp://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/RB1http://en.wikipedia.org/wiki/Code_forhttp://en.wikipedia.org/wiki/Phosphoproteinhttp://en.wikipedia.org/wiki/Phosphorylationhttp://en.wikipedia.org/wiki/Kinasehttp://en.wikipedia.org/wiki/PRb_proteinhttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Mutationhttp://en.wikipedia.org/wiki/Pocket_protein_familyhttp://en.wikipedia.org/wiki/Oncogenichttp://en.wikipedia.org/wiki/Human_papillomavirushttp://en.wikipedia.org/wiki/Human_papillomavirushttp://en.wikipedia.org/wiki/Human_papillomavirushttp://en.wikipedia.org/wiki/Human_papillomavirushttp://en.wikipedia.org/wiki/Oncogenichttp://en.wikipedia.org/wiki/Pocket_protein_familyhttp://en.wikipedia.org/wiki/Mutationhttp://en.wikipedia.org/wiki/Cell_cyclehttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/PRb_proteinhttp://en.wikipedia.org/wiki/Kinasehttp://en.wikipedia.org/wiki/Phosphorylationhttp://en.wikipedia.org/wiki/Phosphoproteinhttp://en.wikipedia.org/wiki/Code_forhttp://en.wikipedia.org/wiki/RB1http://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/Retinoblastomahttp://en.wikipedia.org/wiki/Cancerhttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Tumor_suppressor_genehttp://en.wikipedia.org/wiki/Tumor_suppressor_gene


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Cell cycle suppression

pRb prevents the cell from replicating damaged DNA by preventingits progression through the cell cycle into its S, orsynthesis phase orprogressing through G1, orfirst gap phase. pRb binds and inhibitstranscription factors of the E2F family. E2F transcription factors aredimers of an E2F protein and a DP protein. The transcriptionactivating complexes ofE2 promoter-bindingprotein-dimerizationpartners (E2F-DP) can push a cell into S phase. As long as E2F-DP

is inactivated, the cell remains stalled in the G1 phase. When pRb isbound to E2F, the complex acts as a growth suppressor andprevents progression through the cell cycle. The pRb-E2F/DPcomplex also attracts a histone deacetylase (HDAC) protein to thechromatin, further suppressing DNA synthesis
http://en.wikipedia.org/wiki/Synthesis_phasehttp://en.wikipedia.org/wiki/First_gap_phasehttp://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/E2Fhttp://en.wikipedia.org/wiki/Transcription_(genetics)http://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/wiki/Histone_deacetylasehttp://en.wikipedia.org/wiki/Chromatinhttp://en.wikipedia.org/wiki/DNA_synthesishttp://en.wikipedia.org/wiki/DNA_synthesishttp://en.wikipedia.org/wiki/Chromatinhttp://en.wikipedia.org/wiki/Histone_deacetylasehttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/w/index.php?title=E2_promoter-binding%E2%80%93protein-dimerization_partner&action=edithttp://en.wikipedia.org/wiki/Transcription_(genetics)http://en.wikipedia.org/wiki/E2Fhttp://en.wikipedia.org/wiki/Transcription_factorhttp://en.wikipedia.org/wiki/First_gap_phasehttp://en.wikipedia.org/wiki/Synthesis_phase


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Activation and inactivation

pRb can actively inhibit cell cycle progression when it is

dephosphorylated while this function is inactivated when pRb isphosphorylated. pRb is activated near the end ofmitosis (M phase)when a phosphatase dephosphorylates it, allowing it to bind E2F.

When it is time for a cell to enter S phase, complexes ofcyclin-dependent kinases (CDK) and cyclins phosphorylate pRb, inhibiting

its activity.The initial phosphorylation is performed by CyclinD/CDK4,6 and followed by additional phosphorylation by CyclinE/CDK2. pRb remains phosphorylated throughout S, G2 and Mphases.

Phosphorylation of pRb allows E2F-DP to dissociate from pRb and

become active.When E2F is freed it activates factors like cyclins(e.g. Cyclin E and A), which push the cell through the cell cycle byactivating cyclin-dependent kinases, and a molecule calledproliferating cell nuclear antigen, orPCNA, which speeds DNAreplication and repairby helping to attach polymerase to DNA
http://en.wikipedia.org/wiki/Phosphorylationhttp://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Phosphatasehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclinhttp://en.wikipedia.org/wiki/PCNAhttp://en.wikipedia.org/wiki/DNA_repairhttp://en.wikipedia.org/wiki/DNA_polymerasehttp://en.wikipedia.org/wiki/DNA_polymerasehttp://en.wikipedia.org/wiki/DNA_repairhttp://en.wikipedia.org/wiki/PCNAhttp://en.wikipedia.org/wiki/Cyclinhttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Cyclin-dependent_kinasehttp://en.wikipedia.org/wiki/Phosphatasehttp://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Phosphorylation

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Cancer Causation and Development

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