Genetics of cancer can involve mutations in three classes of genes: proto-oncogenes that become activated oncogenes and promote uncontrolled growth; tumor suppressor genes like RB and p53 that normally inhibit cell growth but are inactivated by mutations; and mutator genes involved in DNA repair that increase mutation rates when defective. The two-hit model of cancer explains that mutations in both copies of tumor suppressor genes are required for tumor formation.
INTRODUCTION
HISTORY
GENES INVOLVED IN CANCER
ONCOGENES
TUMOUR SUPPRESSOR GENES
ONCOGENE
INTRODUCTION
TYPES
ACTIVATION OF PROTO ONCOGENES
FUNCTION
TUMOUR SUPPRESSOR GENES
INTRODUCTION
EXAMPLE
RB GENE
TP53 GENE
CONCLUSION
REFERENCES
Cancer is mainly caused by the conversion of proto-oncogenes into oncogenes. The process is known as oncogenesis.
This slide will help to get an idea about oncogenesis and also the proto-oncogenes which get converted.
In principle, anti-growth signals can prevent cell proliferation by several complementary mechanisms.
The signal may cause dividing cells to enter G0, where they remain until external cues prod their re-entry into the proliferative pool.
Alternatively, the cells may enter a postmitotic, differentiated pool and lose replicative potential.
Non-replicative senescence, is another mechanism of escape from sustained cell growth.
And, as a last-ditch effort, the cells may be programmed for death by apoptosis.
Therefore, tumor suppressor genes have all these “tricks” in their toolbox designed to halt wayward cells from becoming malignant.
ONCOGENE AND PROTOONCOGENE
P53 GENE AND ITS APPLICATION IN CANCER ETIOLOGY
TUMOUR SUPPRESSOR GENE AND BCA AND BAC GENE AND ITS APPLICATION ON THE APOPTOSIS AND DEATH RECEPTORS
INTRODUCTION
HISTORY
GENES INVOLVED IN CANCER
ONCOGENES
TUMOUR SUPPRESSOR GENES
ONCOGENE
INTRODUCTION
TYPES
ACTIVATION OF PROTO ONCOGENES
FUNCTION
TUMOUR SUPPRESSOR GENES
INTRODUCTION
EXAMPLE
RB GENE
TP53 GENE
CONCLUSION
REFERENCES
Cancer is mainly caused by the conversion of proto-oncogenes into oncogenes. The process is known as oncogenesis.
This slide will help to get an idea about oncogenesis and also the proto-oncogenes which get converted.
In principle, anti-growth signals can prevent cell proliferation by several complementary mechanisms.
The signal may cause dividing cells to enter G0, where they remain until external cues prod their re-entry into the proliferative pool.
Alternatively, the cells may enter a postmitotic, differentiated pool and lose replicative potential.
Non-replicative senescence, is another mechanism of escape from sustained cell growth.
And, as a last-ditch effort, the cells may be programmed for death by apoptosis.
Therefore, tumor suppressor genes have all these “tricks” in their toolbox designed to halt wayward cells from becoming malignant.
ONCOGENE AND PROTOONCOGENE
P53 GENE AND ITS APPLICATION IN CANCER ETIOLOGY
TUMOUR SUPPRESSOR GENE AND BCA AND BAC GENE AND ITS APPLICATION ON THE APOPTOSIS AND DEATH RECEPTORS
An oncovirus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, often called oncornaviruses to denote their RNA virus origin. It now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with "tumor virus" or "cancer virus".
This presentation elaborates the economic crisis in Sri Lanka. It explains the causes of economic instability in Sri Lanka and the factors worsening it. Such miserable economic situation is presenting valuable lessons for other sister asian countries to counter their economic instability. Pakistan, a sister country of Sri Lanka is facing severe political and economic instability these days. Pakistan is learning from the Sri Lankan economic situation and tending to improve its economy but the extreme political instability is hurdling and exacerbating the economic crisis. However, policies are underway to counter the economic crisis and more probably Pakistan will escape the Sri Lankan experience.
Toxic effects of heavy metals : Lead and Arsenicsanjana502982
Heavy metals are naturally occuring metallic chemical elements that have relatively high density, and are toxic at even low concentrations. All toxic metals are termed as heavy metals irrespective of their atomic mass and density, eg. arsenic, lead, mercury, cadmium, thallium, chromium, etc.
Salas, V. (2024) "John of St. Thomas (Poinsot) on the Science of Sacred Theol...Studia Poinsotiana
I Introduction
II Subalternation and Theology
III Theology and Dogmatic Declarations
IV The Mixed Principles of Theology
V Virtual Revelation: The Unity of Theology
VI Theology as a Natural Science
VII Theology’s Certitude
VIII Conclusion
Notes
Bibliography
All the contents are fully attributable to the author, Doctor Victor Salas. Should you wish to get this text republished, get in touch with the author or the editorial committee of the Studia Poinsotiana. Insofar as possible, we will be happy to broker your contact.
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...University of Maribor
Slides from talk:
Aleš Zamuda: Remote Sensing and Computational, Evolutionary, Supercomputing, and Intelligent Systems.
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Inter-Society Networking Panel GRSS/MTT-S/CIS Panel Session: Promoting Connection and Cooperation
https://www.etran.rs/2024/en/home-english/
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
What is greenhouse gasses and how many gasses are there to affect the Earth.moosaasad1975
What are greenhouse gasses how they affect the earth and its environment what is the future of the environment and earth how the weather and the climate effects.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
1. Genetics of cancer
Cell cycle and cancer
Two-hit mutation model
Oncogenes and RNA/DNA tumor viruses
Tumor suppressor genes
Mutator genes
Carcinogens: chemicals and radiation
2. Some basic terminology:
Oncogenesis = process of initiation of tumors (cancer) in an organism
(onkos = mass; genesis = birth)
Tumor = tissue composed of cells that deviate from normal program of
cell division and differentiation.
Benign tumor = tumor cells remain together in a single mass and do not
invade or disrupt surrounding tissues
Malignant tumor = tumor cells invade and disrupt surrounding tissues
(diagnosed as cancer, and such cells can transform other cells to the
cancerous state).
Metastasis = spread of malignant tumor cells throughout the body
(typically through the blood and lymphatic system)
3. How do we define cancer?
Cancer is a group of disorders that causes cells to escape
normal controls on cell division
-cancer cells divide more frequently
-cancer cells are not inhibited by contact with
other cells and can form tumors
-cancer cells can invade other tissues, a
process called metastasis
5. Oncogenesis arises from:
1. Spontaneous gene or chromosome mutations.
2. Exposure to mutagens or radiation.
3. Activity of genes introduced by tumor viruses.
4. Some cancers are inherited (individuals may be predisposed).
6. Cell cycle and cancer:
Cell differentiation occurs as cells proliferate to form tissues.
• Cell differentiation correlates with loss of ability to proliferate;
highly specialized cells are terminally differentiated.
• Terminally differentiated cells have a finite life span, and are
replaced with new cells produced from stem cells.
• Stem cells are capable of self-renewal; cells divide without
undergoing terminal differentiation.
Cell death (apoptosis) is equally important.
• Apoptosis is the normal outcome for most cells, and the sequence of
events must be programmed correctly.
• Otherwise cells don’t die when they should, and uncontrolled cell
division can result in cancer.
7. Chemical Signals that Control the Cell Cycle
1. Cyclin and Kinase
-proteins that initiate mitosis
-requires buildup of cyclin to pair with kinase
2. Hormones
-chemical signals from specialized glands
that stimulate mitosis
3. Growth Factors
-chemical factors produced locally that stimulate mitosis
8. Normal cell cycle is controlled by signal transduction:
• Growth factors bind to surface receptors on the cell; transmembrane
proteins relay information to the cell by signal transduction.
• Two types of growth factors:
1. Growth factors stimulate cell division.
2. Growth-inhibiting factors inhibit cell division.
• Healthy cells divide only when growth factor and growth-inhibiting
factor balance favors cell division.
• Cancer cells divide without constraint
• Cancer is primarily caused by mutations in growth and growth-
inhibiting factor genes, and pathways that inhibit the normal
sequence of events associated with apoptosis.
10. Ras Proto-OncogeneRas Proto-Oncogene
In response to growth factor
binding at receptor, the Ras
gene product combines with
GTP to promote cell division
In cancer cells, the RAS
gene product is locked into
its GTP-binding shape and
does not require a signal at
the receptor in order to
stimulate cell division
11. Two-hit mutation model for cancer:
• Most cancers result from mutations in cellular genes.
(other cancers are caused by viruses)
• Two types of cancer:
• Sporadic more frequent, no hereditary cause
• Familial less frequent, hereditary
• Retinoblastoma (OMIM-180200) shows sporadic and hereditary forms
and fits the pattern of a two-hit model.
• Most common eye tumor of children.
• Occurs from birth to 4 years of age.
• Early treatment with gamma radiation is 90% effective.
12. Two-hit mutation model for retinoblastoma (OMIM-180200):
Sporadic retinoblastoma
• 60% of retinoblastoma cases.
• Develops in children with no family history.
• Occurs in one eye.
Hereditary retinoblastoma
• 40% of retinoblastoma cases.
• Onset typically is earlier than sporadic cases.
• Multiple tumors involving both eyes.
• Consistent pedigrees; siblings and offspring develop the same
type of tumors.
13.
14. Alfred Knudson’s (1971) model for retinoblastoma (OMIM-180200):
• Two mutations are required for the development of retinoblastoma.
Sporadic retinoblastoma
• Child starts with two wild type alleles (RB+/RB+).
• Both alleles must mutate to produce the disease (RB/RB).
• Probability of both mutations occurring in the same cell is low;
only one tumor forms (e.g., one eye).
Hereditary retinoblastoma
• Child starts with heterozygous alleles (RB/RB+).
• Only one mutation is required to produce disease (RB/RB).
• Mutations resulting in loss of heterozygosity (LOH) are more
probable in rapidly dividing cells, and multiple tumors occur
(e.g., both eyes).
16. Alfred Knudson’s (1971) model for retinoblastoma (OMIM-180200):
• Retinoblastoma was mapped to the long arm of chromosome 13
(13q14.1-q14.2).
• Mutations occur in a gene that encodes a growth inhibitory factors (a
tumor suppressor gene).
• Retinoblastoma is rare among cancers; most cancers result from a
series of mutations in many different genes.
• So retinoblastoma is easier to treat.
17. Cancer and genes:
Three classes of genes frequently are mutated in cancer:
• Proto-oncogenes (⇒ oncogenes)
• Tumor suppressor genes
• Mutator genes
18. Proto-oncogenes ⇒ oncogenes:
Proto-oncogenes
• Proto-oncgenes are genes that possess normal gene products and
stimulate normal cell development.
Oncogenes
• Oncogenes arise from mutant proto-oncogenes.
• Oncogenes are more active than normal or active at inappropriate
times and stimulate unregulated cell proliferation.
Some tumor viruses that infect cells possess oncogenes:
• RNA tumor viruses = possess viral oncogenes
capable of transforming cells to a cancerous state.
• DNA tumor viruses = do not carry oncogenes, but induce cancer
by activity of viral gene products on the cell
19. Proto-oncogene and oncogene protein products:
• ~100 different oncogenes have been identified.
• To understand the cancer, must understand the function of protein
products coded by the proto-oncogenes.
• All known proto-oncogenes are involved in positive control of cell
growth and division.
• Two classes:
• Growth factors, regulatory genes involved in the control of cell
multiplication.
• Protein kinases, add phosphate groups to target proteins,
important in signal transduction pathways.
• Mutations relax cell control of growth, allowing unregulated
proliferation.
20. Retroviruses and oncogenes:
Retrovirus =
• Single-stranded RNA virus that replicates via double-stranded
DNA intermediate.
• RNA is converted to cDNA by reverse transcriptase.
• DNA integrates into host chromosome and is transcribed.
• Retroviruses typically possess:
• 2 copies of a 7-10 kb ssRNA genome
• protein viral core
• glycolipid envelope (glycoproteins recognize host cells)
• Transducing retroviruses possesses oncogenes, which can cause
cancer when integrated into the host chromosome.
22. Retroviruses and oncogenes:
• All RNA tumor viruses are retroviruses.
• RNA viral oncogenes are altered forms of normal host genes that
occur in the virus genome.
• Examples of retroviruses include:
• Rous sarcoma virus (RSV), Feline leukemia virus, Mouse
mammary tumor virus
• Human immunodeficiency virus (HIV)
• Not all retroviruses are transducing or cause cancer.
23. Life cycle of a retrovirus:
First characterized in 1910 by F. Peyton Rous from a chicken tumor, later
named the Rous sarcoma virus.
1. ssRNA genome is released from the virus particle and is reverse
transcribed to dsDNA (proviral DNA).
2. Reverse transcriptase occurs in the virus particle and lacks 3’ to 5’
exonuclease activity (no proofreading ⇒ lots of mutations).
3. Proviral DNA and host chromosome DNA cross-over and are joined by
recombination.
4. Host RNA polymerase transcribes proviral DNA and produces viral
mRNAs required for the virus life cycle.
25. Cell Cycle Checkpoints
G1S
G2
cytoplasm
doubles
chromosomes
replicate
assembly of
components
for division cytokinesis
P M
A
T
Mitosis
DNA DamageDNA Damage
CheckpointsCheckpoints
DNA DamageDNA Damage
CheckpointCheckpoint
ApoptosisApoptosis
CheckpointCheckpoint
SpindleSpindle
AssemblyAssembly
CheckpointCheckpoint
26. Genetic Mutations That Can Cause Cancer
Tumor Suppressor Genes
• Genes that inhibit cell division are inactivated.
– Mutation in a gene that halts the cell cycle in G1 causes
retinoblastoma.
– Mutation in p53, a gene that promotes apoptosis if a cell has
damaged DNA, leads to a variety of cancers.
– Mutation in BRCA1, involved in tumor suppression and DNA
repair, leads to inherited breast cancer.
27. In Normal Cells, the Rb Gene ProductIn Normal Cells, the Rb Gene Product
Controls the G1Controls the G1 S TransitionS Transition
Rb = product of
Retinoblastoma gene,
inhibits action of E2F until
chemically modified
People prone to retinoblastoma have one mutated copy of the RbPeople prone to retinoblastoma have one mutated copy of the Rb
gene (Rb-) and one normal copy (Rbgene (Rb-) and one normal copy (Rb++
). Conversion of the Rb). Conversion of the Rb++
copycopy
to Rbto Rb--
by mutation leads to uncontrolled growth of retinal cells.by mutation leads to uncontrolled growth of retinal cells.
E2F = transcription factor
required to activate genes
for DNA synthesis
CDK-cyclin (intracellular
signal) modifies Rb so
the E2F can mediate the
G1S transition
28. In Normal Cells, the p53 Gene ProductIn Normal Cells, the p53 Gene Product
Acts at the G1Acts at the G1 S Checkpoint PreventingS Checkpoint Preventing
Entry Into S Phase If DNA Is DamagedEntry Into S Phase If DNA Is Damaged
p21 inhibits intracellular signals
that would activate EF2
p53 = transcription factor that
causes p21 to be produced
Cells with
damaged DNA
do not pass the
G1S
checkpoint
In cancer cells the mutated p53 gene
product no longer stimulates p21
production. Cells will pass the G1 S
checkpoint even when chromosomal
damage exists.
29. In Normal Cells, the p53 Gene Product StimulatesIn Normal Cells, the p53 Gene Product Stimulates
Apoptosis If DNA Damage Cannot Be RepairedApoptosis If DNA Damage Cannot Be Repaired
p53 gives an internal
signal for apoptosis
In cancer cells, a mutated p53
gene product no longer initiates
self-destruction. Cells with
damaged DNA can divide and
more DNA damage can be
accumulated.
p53 is the most frequently mutated
of all known cancer-causing genes,
contributing to many types of cancer.
30. p53 tumor suppressor genes:
• Mutations in p53 are implicated in ~50% of human cancers,
including cancers of the:
breast, brain, liver, lung, colorectal, bladder, and blood
• Development of tumors requires mutations on two p53 alleles.
• Codes a 393 amino acid protein involved in transcription, cell cycle
control, DNA repair, and apoptosis (programmed cell death).
• p53 binds to several genes and interacts with at least 17 cellular
and viral proteins.
31. Genetic Mutations That Can Cause CancerGenetic Mutations That Can Cause Cancer
DNA Repair GenesDNA Repair Genes
• Genes that promote DNA repair are inactivated.Genes that promote DNA repair are inactivated.
– BRCA1 is a tumor suppressor involved in DNA repair. FaultyBRCA1 is a tumor suppressor involved in DNA repair. Faulty
copies of BRCA1 cause inherited breast cancer.copies of BRCA1 cause inherited breast cancer.
– The disease Xeroderma Pigmentosum results from a defect inThe disease Xeroderma Pigmentosum results from a defect in
excision repair.excision repair.
32. Breast cancer tumor suppressor genes:
• Breast cancer affects 1 in 10 women and represents 31% of
cancers in women (~185,000 women diagnosed each year).
• ~5% of breast cancers are hereditary; age of onset for hereditary
breast cancer is earlier than other forms (mutations at 2 alleles).
• Many genes involved; BRCA1 and BRCA2 are thought to be tumor
suppressor genes.
• BRCA1 is important for homologous recombination, cellular repair
of DNA damage, and transcription of mRNA.
• Mutations in BRCA1 also are involved in ovarian cancer.
• BRCA2 plays a role in timing of mitosis in the cell cycle.
33. Mutator genes:
• Mutator gene increases spontaneous mutation rate of other genes.
• Mutator gene products are involved in DNA replication and repair;
mutations make the cell error prone.
• HNPCC-OMIM 120435, Human non-polyposis colon cancer
• Mutation at any one of 4 genes (hMSH2, hMLH1, hPMS1,
hPMS2) leads to predisposition.
• Tumor formation requires mutation at the second allele.
• All four genes have homologs in yeast.
• DNA blood tests are available for all four genes.