P53 tumor suppressor protein

Basics of Cancer Biology

• Cancer is characterized by the uncontrolled growth of cells.
• Three hallmarks of cancer cells are immortalization, transformation, and metastasis.

Types of Cancer

• Benign and malignant are two broad classifications.
• Leukemia is marked by the overproduction of leukocytes.
• Sarcoma is cancer of muscle and cartilage tissue.
• Carcinoma originates from cancers of epithelial tissue like glands, breast and skin.
• Mesothelioma is derived from mesothelial cells lining the peritoneum.
• Glioma is derived from glial cells.
• Germinoma arises from germ cells normally in the testicles and ovaries.
• Choriocarcinoma is cancer of the placenta.

Oncogenes

• Oncogenes promote tumor formation and an example is v-onc, the first one discovered from the Avian Sarcoma Virus (src).
• Proto-oncogenes are normal cellular genes that can cause cancer under altered conditions.
• Tumor suppressor genes restrain cell proliferation, like Rb and p53.

Oncogene Discovery

• Shotgun cloning was used.
• ras was discovered from bladder carcinoma.
• met was discovered from hepatocarcinoma.
• hst was discovered from stomach carcinoma.
• Oncogenes can be screened using probes.

Changes When a Cell Becomes Cancerous

• Oncogenesis is the process of malignant transformation that leads to cancer.
• Cancer cells lose their growth control.
• Cells can undergo changes such as immortalization, transformation, and metastasis.
• Immortalization leads to indefinite growth.
• Transformation results in deviation from normal growth requirements.
• Metastasis is the invasion of normal tissues.
• Normal cells in vitro will undergo senescence and cease growth, leading to crisis.
• Immortalization occurs after surviving crisis.
• Immortalized cells are non-tumorigenic but still depend on anchorage and growth factors.

Proto-oncogene Activation

• Proto-oncogene activation can cause cancer.
• Activation generates oncogenes.
• Can be the result of mutational change or overexpression.
• Oncogene protein products include transcription factors and transmembrane proteins.

Transformed Cell Properties

• Transformed cell lines are derived from tumors.
• They exhibit more changes than immortalized cell lines.
• Grow in less restricted conditions and have reduced reliance on growth factors.
• They have less anchorage dependence, forming foci instead of monolayers and are tumorigenic.

Genetic Changes in Cancer Cells

• Conversion of normal cells to transformed cells requires multiple genetic alterations.
• It takes 6-7 events over approximately 40 years.
• Factors like carcinogens increase the rate of conversion.
• Genes that cause transformation are oncogenes (100+) and tumor suppressor genes (~10).

Transforming Viruses

• Transformation results from tumor virus infection.
• Tumor viruses with DNA can inactivate tumor suppressor genes.
• Polyomavirus and Adenovirus are examples (dsDNA).
• Human papillomavirus (dsDNA) inactivates tumor suppressor gene.
• Retroviruses with RNA activate oncogenic pathways.

Common Mechanism of DNA Tumor Virus Transformation

• Early genes possess oncogenic potential.
• Viral oncogenes integrate into the host genome.
• Oncogene proteins interact with host cellular proteins.
• Polyoma & SV40 produce T-antigens which have transforming activity.
• Papillomaviruses produce E6 & E7 oncoproteins.
• EBV can cause lymphoproliferative disorders and immortalizes human B lymphocytes.

Retroviruses

• Can transfer transforming genes vertically and horizontally.

• Requires reverse transcription for viruses with RNA genomes.

• Non-defective tumor retroviruses ability to transform depends upon its effects on expression of host genes at its site of insertion into the cellular genome:

• Examples: Leukemia virus (FLV) which has no viral oncogene; viral activation of cellular proto-oncogene.

• Acute transforming tumor retroviruses are captured new genes in the form of oncogenes (cellular origin).

• Rare event, cannot replicate by itself and needs helper virus.

Retroviral Oncogenes

• The normal cellular sequence itself is not oncogenic.
• The difference between oncogenes & proto-oncogenes: Changes in v-oncogenes.
• Retrovirus capture of the proto-oncogene (c) results in oncogene (v).
• More than 30 c-onc genes have been identified.
• Rous Sarcoma Virus carries v-src gene

Basics of Cancer (Genetic Origins and Development)

• Cancer is a genetic disease due to alterations in specific genes.
• It is usually not an inherited disease.
• Genetic alterations leading to cancer arise in somatic cells during an individual’s lifetime.
• Cancer cells proliferate uncontrollably and malignant tumors invade surrounding tissue.
• Malignant tumors metastasize, spreading to distant sites and establishing lethal secondary tumors.
• The incidence of cancer has been a research focus for decades, aiming to prevent and cure it, treatments can involve harsh chemicals.

Basic Properties of Cancerous Cells

• Cancer cells are obtained from malignant tumors.
• The tissue is dissociated and cultured in vitro, allowing for study.
• Normal cells can be converted to cancer cells through carcinogenic chemicals, radiation or tumor viruses.
• Cells transformed in vitro by chemicals or viruses can cause tumors when introduced into a host animal.
• Cancer cells exhibit loss of growth control.
• When normal cells grow in tissue culture, they divide at a rate similar to malignant cells.
• Normal cells stop proliferating when they cover the dish, as their growth rates drop responding to inhibitory signals.
• Malignant cells continue to grow, forming clumps, as they are not responsive to growth cessation signals.
• Cancer cells continue to grow in the absence of inhibitory signals and require serum to grow.

Properties of Cancerous Cells cont.

• Normal cells exhibit a limited capacity for cell division.
• Cancer cells are seemingly immortal.
• The presence of telomerase accounts for the difference in growth potential.
• Telomerase maintains telomeres at the ends of chromosomes which allows cells to continue to divide.

Properties of Cancerous Cells cont.

• Normal cells maintain their diploid chromosomal complement.
• Cancer cells are genetically unstable, exhibiting aneuploidy.
• Cancer cells have less dependence on standard diploid chromosome content than normal cells.
• Normal cells activate a signalling pathway leading to self destruction (apoptosis) when cells are disturbed.
• Cancer cells typically fail to elicit apoptotic responses.
• Cancer cells depend on glycolysis an anaerobic metabolic pathway.

Causes of Cancer

• In 1775, Percivall Pott identified a correlation between environmental agents and cancer.
• Carcinogenic chemicals, radiation, and viruses can cause cancer.
• All these agents alter the genome.

Causes of Cancer Cont.

• Viruses include DNA viruses and RNA viruses.
• DNA viruses include polyoma virus, simian virus 40 (SV40), Human papilloma virus (E6 and E7) and adenovirus (E1A and E1B).
• Tumor viruses carry genes that interfere with normal growth regulating activities.
• Tumor viruses are associated with human cancers.
• HPV can be transmitted through sexual activity, and is linked to 90% of cervical cancers.
• Vaccines are available for HPV.
• Other viruses associated include Hepatitis B and the Epstein Barr virus.

Causes of Cancer Cont.

• Helicobacter Pylori is also responsible for certain gastric Lymphomas.
• Infections can be caused by chronic inflammation because of the presence of a pathogen.
• Inflammatory bowel disease (IBD) has an increased risk of colon cancer.

Genetics of Cancer cont.

• Cancer is a leading cause of death, and arises from a single, genetically altered cell (monoclonal).
• Malignant transformation requires multiple genetic alterations.
• Germ-line mutations are inherited from parents, somatic mutations occur during one's lifetime.

Tumor Suppressor Genes

• Tumor-suppressor genes act as a cell’s brakes.
• They encode proteins that restrain cell growth and prevent cells from becoming malignant.
• Studies in the 1960s had normal and malignant rodent cells fused, suggests that normal cells possess factors that can suppress the uncontrolled growth of a cancer cell.
• Evidence from observations that specific regions of particular chromosomes are consistently deleted in cells of certain types of cancer.

Proto-oncogenes vs Oncogenes

• Oncogenes encode proteins that promote the loss of growth control and convert cells to a malignant state.
• They may lead to genetic instability, prevent cell death, or promote metastasis.
• Tumor viruses transform normal cells into malignant cells because they carry an oncogene.
• They encode a protein encoded by avian sarcoma virus that interferes with the cell's normal activities.
• In 1976, it was discovered that discovered that an oncogene called src.
• It was not a viral gene, but a cellular gene was present in the genome of uninfected cells. Cells possess a variety of genes, referred to as protooncogenes, that have the potential to subvert the cell's activities and push it toward malignancy.

Protooncogene:

• Cellular normal gene that causes cancer under altered conditions.

Tumor Suppressor Genes Cont.

• Transformation of a normal cell into a cancer cell involves loss of function for one/more tumor-suppressor genes.
• More than two dozen tumor suppressors implicated in humans include TP53.
• Proteins encoded by tumor-suppressor genes act as negative regulators of cell proliferation; their elimination promotes uncontrolled cell growth.

Tumor Suppressor Gene: RB

• Rare inherited cancer syndromes are an opportunity to identity tumor suppressor genes that, when missing, contribute to both inherited and sporadic forms of cancer.
• The first tumor-suppressor gene is associated with childhood cancer of the retina, retinoblastoma.
• The gene responsible for this disorder is RB.
• This gene can be inherited if the parent had it previously or sporadically appear as result of environmental triggers.
• Examination of cells from children revealed deletion of thirteenth pair homologous chromosomes; a inherited gene

RB Protein

• Retinoblastoma is inherited as a dominant genetic trait because it is present in every cell.
• About 10 percent a chromosome with an RB deletion never develop the retinal cancer.
• People with a soft-tissue, inherited mutation are also at high-rist to inheriting tumors.
• RB alleles are common in retinobalstoma, sporadic prostate, osteo and lung cancers.

Role of pRB In Regulating the Cell Cycle

• Control the cell cycle can play a pivotal role in the development of cancer.
• It helps regulate the passage into phase, during which DNA synthesis occurs.
• The transition from phase is a time of commitment for the cell and needs regulation

p53 Cont.

• TP53 gene codes for p53 protein.
• p53: tumor-suppressor gene + absent causes, Li-Fraumeni: rare inherited disorder
• The victims prone to very high incidence of different cancers, including breast/brain can/leukimia
• Li-Fraumeni syndrome inherit one normal and one abnormal deleted allele TP53. Tumor suppressor gene= susceptible to develop cancers from random mutations in the normal allele.

p53 protein regulates tumor suppression

• Point mutations/deletions in both aleles of the Tp53 gene leads to cancer progression.
• Tumors composed of cells with mutations, are correlated with a poorer survival rate than those containing a wild-type TP53 gene.
• the importance of p53 is evident due to that it’s and important step in cells that lead to cancer and toward the fully malignant state

P53 Protein Function

• p53 is a protein protects cells from DNA damages
• A sensor detects defects in DNA -> arrest or apoptosis
• Has many functions like repairing or desctructing cell with damaged DNA
• The main goal of p53 function essential is ultimate survival!

p53 Protein Structure

• Proteins are all activated via independent
• Activation of cycle or arrest =an alternative to apoptosis.
• Involves in a cell to maintain genome stability.
• p21, an inhibitor is involved arrest cell in G1 phase. damage arrest.

p53 and Apoptosis

• p53 can direct cell cycle when there genetically Damaged cell.
• whether they are moved based on the type of posttranslational modifications- depends on what the cell needs.
• can direct a cell to do different results.

p53 and cell cycle

• ATM kinase is one of the proteins ATM phosphorylates
• The phosphorylated version of the p53 molecule is no longer able to interact with MDM2.
• Some tumor cells found that they contain a wildtype TP53.
• Over expressed MDM2 can prevent the cell to build it up.

p53 Cell Cycle

• A major effort is to develop drugs that restore P53 that has known tumor suppresses, those that are Key tumor suppressor.
• MDM@ has p53 been demonstrated gene knockout, due to that the cells undergo dependent apoptosis.
• An important principle has come because the Embryos are unable to produce p53, they do not need a protein MDM2.
• alterations genes whose produces are part of pathways

FAP

• FAP: inherited disorder, small vasucalr growth on the surface of mucous membrane called adenomas.
• Epithelial cells, that line the colon wall, is called the adenomatous polyposis COli
• can cause a fully malignant stage or fully cancerous situation.
• The cells contain a deletion of a small portion OF chromosome 5.

BRCA1 and 2

• BRCA strikes about approximately 1 inch in 8, most women.
• it only inherited to 5- 10.
• BRCA1 and BCRA2 in the major 90 are located in the Middle 90.
• BRCA can also predispose to woman or the the the.

BRCA 1& 2 continue….

• BRCA2 proteins are part of one or more large proteins with that respond and repair a number of key points that help from cycle following and having damage dna.
• Mutants do not have their, Dna is highly

Oncogenes

• Promote growth, loss of control cells from become malignant
• They are having a normal protein to turn in.
• Proto play a goal in cell growth and divisions
• mutated frequently

Apoptosis

• Apoptosis is is to rid the body for tumor, or malignancy at early stage
• A BCL will be altered if self described is more to increase the chance of tumor.
• The 3K will lead to tumorigenesis.
• Both were encoded and had documented results
• The knock out Mice gene is most clear was to cause the BCI.
• This genes are for a gene has been affected by the normal cells.

Oncogenes product affect apoptosis continued...

Once formed, the lymphoid tissues and the results is wider a spread of apoptosis Myc: The same and high and level cells can cause gene abnormal. Tumor , certain cells can form the gene BCL 2 that is codes for the heavy molecule Leads to expression over expression in all lympoid cells. And is is reducing the use of chemotherapy

PTEN:

• (phosphatidylinositol-3,4,5- trisphosphate 3-phosphatase )

Role in cancer

• The 1R is a gene that caused in several cancers
• In a some situations their anti protiens help other cells.
• The 2ND IFR has the cancer to go up .
• The high levels I fr, signals the cell that needed for more growth and will surive.
• Are are involved in the cardio genesis OF reast cancers.

ATM and ATR

• That is an inherited disease that, is with the diverse symptom, in other cases in the cancer and a heart.

• That is that the radiation and normal cell will then stop. Normal cycle tell the damages has been solved..
  

ATM and ATR continued..

The cycle will have point that need with certain with normal

ATM and ATR.. (Cycle functions)

They get a sensor detected on the is to repair the cancer, but this is in cells can run the risk become a cells..

ATM and ATR cont... (Genes)

The mutated kianse activation. The atp gene coding for for to find Atfter a damage cause by cell with all arrest that lead to damage of ur radiation. they help at the bond site

UV radiation..

• The radiation causes the cell body and with all affect by the cells..
• Help all cycle and all for a damagaed repair.

DNA Rrepaire and oncogenes

• Mutation in the gene leads to increased increase of risk.
• Selectively in the the correct the number correct number for the select the a.i repairs.
  • if defected expect to to be the cause of what can display.. and cancer cell.
• the defien.

DNA repair and oncogene continue.

• defects in in nucleotide exicision reapir the NER -evidence obtainted and the repairs . that the the cells of the petents in the the the for for for for of of colon.
• has defects and responsible to for cacer genes carry.

Damage

• if a normal cells does not get repair and they to get a malignment.

Diseases in which in cell has damaged

• are a hypo sensisitive.
• the cances is a light to skin are affect.

Ataxia Telangiectasia

• AT and has all sensivity they ar are a light to to and all they damage cells and all are sensitve.

Micro RNA and cancer

These are are tiny , that negatively lead , expression of target MN. The high that the level of cause a.to create and to make cancer cause from cancer and all. Can be thought of tumor repenessiations.

• If it lack with all lead all to with apotiosis.
• If the lock it could has all lead to

Mircro RNA and cancelr continue....

• the are used lead to cells to and and high for cells to cells. it create the gene that accounf and is oncreased the to cells. it create a high cause to for the is atumor, cause a high alevel, is at the tumers

Mirror RNA and cancer continue

• The the cell.
• it need need more a resutls that at the to.

Questions about P53 regulation by MDM2, its response to DNA damage, and its role in apoptosis via BAX. It also covers the impact of BRCA proteins on DNA repair.