Unit 1 Exam Ch 1 2 3 Flashcards
(312 cards)
1
Q
Cancer
A
Group of diseases, characterized by unregulated growth
2
Q
Germ Layer
A
a group of cells in an embryo that interact with each
other as the embryo develops and contribute to the formation of all organs and tissues
3
Q
Ten Hallmarks of most cancers
A
Sustained Proliferation Evading growth suppressors Avoiding immune destruction Activating invasion and metastasis Inducing angiogenesis Genome instability and mutation Resisting Cell death Deregulating cellular epigenetics
4
Q
Evading Growth Suppressors
A
Cancer cells do not respond to growth inhibitory signals and acquire mutations that interfere with inhibition
5
Q
Avoiding immune suppression
A
Successful cancer cells may be those that do not
stimulate an immune response or can interfere with the
immune response so as to avoid immune destruction
6
Q
Unlimited replicative potential
A
Normal cells replicate for a certain number of generations and become senescent, after shortening of telomeres (Cancer cells’ telomeres aren’t shortening) and have unlimited replicative potential
7
Q
Tumor-Promoting inflammation
A
• Inflammation is an immune response that can
facilitate the ability of acquiring the core
hallmarks of cancer.
• In addition, inflammatory cells can release
oxygen species that are mutagenic
8
Q
Invasion and Metastasis
A
Cancer cells invade other tissues and migrate to other parts of the body, causing multi-system cancers
9
Q
Invasion and Metastasis
A
Cancer cells invade other tissues and migrate to other parts of the body, causing multi-system cancers
10
Q
Cancer cells induce angiogenesis, growth of new blood vessels, needed for tumor survival. Altering the balance between angiogenic
inducers and inhibitors can activate the
angiogenic switch
A
Sustained Angiogenesis
11
Q
Evading Apoptosis
A
Normal cells are able to be destroyed via apoptosis
Cancer cells evade those mechanisms to continue unregulated growth.
12
Q
Genome instability and mutation
A
Faulty DNA pathways contribute to genome instability
13
Q
Reprogramming energy metabolism
A
Uncontrolled cell division demands increases in
fuel and biosynthetic precursors that is obtained
by adjusting energy metabolism
14
Q
Grows in clusters of cells called foci Do not exhibit contact inhibition Can grow in low serum media Round morphology Exhibit "anchorange independence"
A
Morphology and characteristics of cancer cells
15
Q
Anchorage independence
A
Cancer cells Lose contact with the media and won’t die
16
Q
Benign Tumor
A
No evidence of cancer Does not metastasize Some can be life-threatening well-defined borders well differentiated Lost regulation of the cell cycle
17
Q
Malignant
A
Not encapsulated Invades and metastasized Large, rapid growth Poorly differentiated increased nuclear to cytoplasm ratios Nuclear hyperchromasia and prominent nuclei (stains brightly)
18
Q
Neoplasia
A
New growth, not reversible
19
Q
Dysplasia
A
Disordered growth, often resulting in neoplasia
20
Q
Tumor
A
Abnormal growth, benign or malignant
21
Q
Cancer
A
Malignant neoplasm or tumor that invades nearby tissue
22
Q
benign epithelial tissue
A
adenoma, papilloma
23
Q
beningn mesenchyme tissue
A
Fibroma, Lipoma
24
Q
Benign Melanocytes
A
Nevus (Mole)
25
Benign Lymphocytes
Benign lymphoid hyperplasia
26
Malignant epithelial tissue
Adenocarcinoma
| Papillary carcinoma
27
Malignant mesenchyme tissue
Sarcoma
28
Malignant Melanocytes
Melanoma
29
Malignant Lymphocytes
Lymphoma
30
Breast Cancer Main site of metastasis
Lungs, liver, bones
31
Colon Cancer Main site of metastasis
Liver, peritoneum, lungs
32
Lung Cancer main site of metastasis
Adrenal gland, liver, lungs
33
Melanoma main site of metastasis
Lungs, Skin, muscle, liver
34
Why are the liver and lungs common sites for metastasis?
Blood flows through both organs frequently (Portal vein, lungs)
35
Why are malignant tumors so life-threatening?
Physical obstruction
Invading other organs and compromising their functions
Competing for nutrients, oxygen, and produce waste product
36
Mutation
Alteration of DNA sequence
37
Carcinogen
Agent that causes cancer
38
Mutagen
Agent that causes mutation
| *Not all mutations cause cancer
39
Translolcation
DNA mutations whereby a part of one chromosome is transferred to or exahnged for anohter part of a different chromosome
40
Proliferation
Cell division, cell growth
41
Apoptosis
Programmed cell death
42
Differentiation
cells enter an inactive phase of cell growth and can lead to unregulated cell growth
43
Leukemia
Overproduction of white blood cells or their precursors in the blood or bone marrow
44
Proto-Oncogenes
NOrmal genes that can be activated by mutation to be oncogenic
All normall cells have proto-oncogenes
45
Oncogenes
Mutated genes that produce an increased amount of protein products
46
Characteristics of Oncogenes
Cause increased activity and uncontrolled cell division
Always in "on" state
Platelet dereived growth factor (PDGFR)
Glioblastoma, myeloid leukemia
Acts in a dominant manner to initiate tumor formation (one allele is sufficient for the effect)
47
Tumor Suppressor Genes
Code for proteins that have a role in inhibiting borth growth and tumor formation
48
Tumor Suppressor Genes mode of function
Mutation results in a loss of function of genes that control growth
49
Tumor suppressor genes mode of inheritance (Dominance vs Recessive)
Recessive in nature (both must mutate to lose function)
50
Knudson's Two-Hit Hypothesis
Explains the methods of tumor suppressor genes
States that both alleles must be mutated to trugger carcinogenesis.
Explains certain individuals have an increased risk for cancer
The have inherited a mutated tumor suppressor allele
51
Haploinsufficiency
only one mutated allele can lead to the cancerous phenotype. One allele (normal) produces half the quantity of protein product produced by normal cells, and this is not enough to suppress tumor formation in these cases
52
Stem Cells
Undifferentiated cells that still have the ability to self-renew and produce differentiated progeny
53
Self-Renewal
A stem celll or other progenitor cell gives rise to a new daughter cell with equivalent developmental potential.
54
Environmental factors contributing to human carcinogenesis
UV radiation, toxins, form pyrimidine dimers and cause mutations
55
Reproductive life influential factors contributing to human carcinogenesis
Age of menstruation, and age of reproduction in women, contraception and fertility treatments alter ovulation, HPV, HIV, Kaposi's Sarcoma, HSV 8
56
Diet and Exercise influential factors contirbuting to human carcinogenesis
Breast cancer can be reduced by 25%, certain diets from certain regions increase certain cancers
57
Alcohol influential factors contributing to human carcinogenesis
Max intake 28g, accounts for 389,000 cases in the U.S per year (Mouth, Esophageal, breast, and Liver cancer)
58
Smoking influential factors contributing to human carcinogenesis
Causes lung, pancreatic, bladder, kindey, mouth, stomach, and liver cancer. Accounts for 40% of all cancer deaths
Lung cancer is the main cancer worldwide
59
Number of carcinogens found in cigarette smoke
81
60
Additional Influences contributing to human carcinogenesis
LIfespan o the cell, free radicals, disorders related to metabolism
61
Red meat contributes to cancer development
Increases lumenal carcinogens through home, micronbial metabolism of protein rescues and barbequeing heterocyclic amines
62
How does fat contribute to cancer development?
Induces hepatic synthesis of bile acids; clonoc microbes covert Ba to 2YBA= Carcinogenic
63
Fruit and Vegetables' affect on cancer development
Suppresses colon cancer due to antioxidant and antineoplastic properties (Vitamin C, folate), selenium, calcium, and bioactive phytochemical compounds
64
Rate of Colon cancer for African People
Less than 5 per 100,000
65
Marijuana's affects on cancer cells
THC and other cannabinoids slow grouth and reduce spread of some forms of cancer
66
Types of Cancer Therapies
Cytostatic and cytotoxic
67
Cytostatic Cancer therapy
Halts proliferation
68
Cytotoxic Cancer Therapy
Kills the cancer cells
69
How to determine what the best drug or treatment is for cancer
THe best drug is the one that can be used in the lowert dose with minimal side effects
70
Therapeutic index
Value between the minimum effective dose and maximum tolerated dose
The larger the value, the better the drug
Many Drugs are given at the MTD (Maximum tolerated dose)
71
easiest method of cancer treatment
Surgery
Works for some cancers, not others
Does not address metastasis
72
Chemotherapy Methods of treatment
Target DNA, RNA, and Protein to disrupt the cell cycle
73
Main aim of chemotherapy treatments
Cause DNA Damage and trigger apoptosis
74
Side effects of Chemotherapy
Alopecia, ulcers, anemia
75
Interventional Studies (Clinical Trial)
Research subjects are assigned to a treatment or intervention and their outcomes are measured (Phase 1-4)
76
Phase I clinical trial
Researchers test an experimental drug or treatment in a small group of people (20-80) for the first time. Evaluates safety, dosage, and range. Identifies side effects
77
Phase II Clinical trial
Larger group (100-300), determines if it's effective and further evaluates safety
78
Phase III Clinical Trial
1,000 to 3,000 participants to confirm effectivness, monitor side effects, compare to commonly used treatments, and collect information for safety
79
Phase IV clinical Trial
Post-marketing studies delineate additional ifo including drug's risk, benefits, and optimal use
80
Gene
a specific stretch of DNA that programs the amino acid sequence of a polypeptide
81
4 parts of a gene
Promoter
Terminator
Start codon
Stop Codon
82
Operon
Cluster of genes under the control of the same promoter
83
True or false: Operons only occur in Eukaryotic organisms
FALSE:
| Operons only occur in prokaryotes
84
3 Parts of a nucleotide
5-Carbon Sugar
Phosphate group
NItrogenous Base
85
Purines
Adenine
| Guanine
86
Pyrimidines
Cytosine
Thymine
Uracil
87
Which is more stable: DNA or RNA?
DNA is more stable, which is why RNA organisms are typically viruses and require a host
88
Mutations can be
Environmental or Endogenous processes during metabolism
89
Causes of mutation
Toxins (Asbestos)
Smoking
UV Light
Radiation
90
Central Dogma
DNA to RNA to Protein
91
Intron
Non-COding DNA Sequence, splicing removes them
92
Exon
Coding region of DNA
93
Spliceosome
a large RNA-protein complex that catalyses the removal of introns from nuclear pre-mRNA.
94
Translation
Synthesis of a protein from an MRNA template
95
Steps of Translation
Initiation (3' Poly A tail added)
Elongation ( add 1 amino acid down the mrna to grow the polypeptide chain
Termination( Add 5' Methylated cap)
96
TRNA
Anticodon complimentary to the MRNA
97
AUG
Methionine (Universal Start codon)
98
What makes the MRNA release from the ribosome TRNA complex
STOP CODON
99
polycistronic
two (bicistronic/dicistronic), three (tricistronic), or more separate proteins are encoded on a single molecule of messenger RNA (mRNA). In prokaryotes, polycistronic expression is commo
100
Which region of DNA is involved in regulating the expression of genes?
Promotor Region
101
The promotor region controls
When and where a gene is expressed and interacts with proteins that affect the activity of RNA polymerase
102
TATA Box CODing Sequence
TATAAA
103
TATA BOX (Definition)
An important rgulatory element for most genes
Located neae the start site of transcription
Binding of TATA Box Binding Protein (TBP) is important for initiation of transcription
104
Response element (RE)
Short sequence of DNA within the promoter that is recognized by a specific protein and contributes to the regulation of the gene
105
Response element can either be
Enhancer Element (EE) or Inhibitor Element (IE)
106
Mutations
Alterations in DNA Sequence
| Base subsititutions can lead to Amino acid change or may be silent
107
Silent mutation
Does not affect Amino Acid Sequence
108
Missense Mutation
Amino Acid changes, polypeptide changes, structure and function of the protein is affected
109
Nonsense Mutation
Inadvertently causing a stop codon to be produced, stops translation early, and the polypeptide is incomplete
110
STOP CODONS
UAA
UAG
UGA
(DO not code for an Amino Acid)
111
Start codon
Methionine
112
Frameshift mutation
Addition or deletion
| changes the reading frame and loss in gene functions
113
Diseases which cause Frameshift mutations
HIV
HTLV
They integrate into the genome and shut down functionality
114
Transitions
Substitution of one purine for another purine or
| substitution of one pyrimidine for another pyrimidine
115
Transversions
T to A or G (Pyrimidine to Purine)
C to G or A (Pyrimidine to Purine)
A to T or C (Purine to Pyrimidine)
G to C or T (Purine to Pyrimidine)
116
Translocation
Exchange of part of one chromosome with a part of another chromosome
117
Burkitt's Lymphoma Translocation
8: 14
118
Acute Myeloblastic Leukemia Translocation
8:21
119
Gene Amplification
Similar to translocation, but only at one gene in the same location
120
Example of gene amplification
Elephants have 20 copies of p53 gene, and have only a 5% cancer rate because the cells kill the cancer quickly
121
Chromothripsis
When fragments of single shattered chromosomes are peiced together
122
Chromothripsis is common in
Bone Cnacers
123
3 Possible reasons for chromothripsis
Ionizing radiation that leads to chromosome breaks
Telomere Defunction which may lead to end-end chromosome fusions
Aborted apoptosis such that cells which have initiated DNA Fragmentation push through and survive
124
DNAse
Enzyme that chops up DNA and those pieces could get picked up and annealed together
125
Consequence of mutation
In a gene is determiend by its location with respect tot to functional parts of the genes
126
Mutations in the promotor or regulatory region
Can alter regulation and affect levels of gene product, and halt transcription
127
Driver mutations
Located in cancer genes by definition
| Confer a growth advantage on cells
128
Passenger Mutations
Do not confer a growth advantage
| are there for the ride
129
Carcinogenic agents
Radiation
Chemicals
INfectious Pathogens
Endogenous Reactions
130
2 forms of radiation energy
Waves (Electromagnetic radiation)
| Stream of atomic Particles ( alpha and beta) particles
131
Electromagnetic spectrum
```
Radio Waves
Microwaves
Infared
Visible Light
Ultraviolet LIght
X-Rays
Gmamma Rays
```
132
EM Spectrum that's considered ionizing radiation
UV Light
X-Rays
Gamma Rays
(Can cause Double-Stranded DNA Breaks)
133
LET (Low-Energy Transfer)
Rate at which the energy is released
| The amount of energy released by a radiation source as it travels a fixed distance
134
High-LET Radiation (Alpha Particles)
Emit more energy than Low-LET radiation (X-Rays) over the same distance
135
Radon Gas is considered
A Category 1 Carcinogen
136
Category 1 Carcinogens
Radon Gas
Asbestos
Tobacco
Mustard Gas
137
Cancers associated with high-dose radiation exposure
Leukemia, Breast, Bladder, liver, lung, esophageal, ovarian, multiple myeloma, and stomach cancers
138
Most common Ionizing Radiation Cancer
Leukemia
| Children are most often affected
139
Risks of solid tumor increase in linear fashion based on
an increased dose of radiation
140
Biological effects of Ionizing Radiation
Injured cells repair themselves, no residual damage
Cells die, being replaced through normal biological processes (apoptotic processes)
Cells incorrectly repair themselves, resulting in a biophysical change (and pass on the mutation)
141
Dose of 10,000 mSV
Single dose, fatal within weeks
142
Dose of 5,000 mSV
1/2 killed within a month
143
Dose of 1,000 mSV
Radiation sickness, nausea
144
Dose of 100 mSV
Radiation workers every 5 years
145
Dose of 16 mSV
CT of the heart
146
Dose of 10 mSV
CT of the body
147
Dose of 2 mSV
Radiation of most people
148
Dose of .01 mSV
Dental X-Ray
149
Ionizing Radiation includes
Alpha Particles
Beta Particles
Gamma Rays
150
Characteristics of Ionizing Radiation
Convert electrically neutral molecules into ions
| Cause radiolysis generating intermediates called reactive oxygen species (ROS)
151
ROS
May react with DNA or with other biomolecules and cause damage
152
Free radicals
considered potent carcinogens because they can cause oxidation of DNA by oxidizing DNA bases
153
Characteristics of Ultraviolet Radiation
SHorter wavelength and higher energy than visible light
| Affects human health both positively and negatively
154
What protects the Earth from UV Radiation
Stratospheric Ozone Layer
155
UV Radiation that passes through the Ozone layer can cause
Skin Cancer
Cataracts
Suppression of the immune system
Premature aging
156
Vitamin D and UV Radiation
UV Radiation provides Vitamin D, and a deficiency can result in Ricketts
157
Fluorochlorocarbon (CFCs)
Gases that break down Ozone layer
Converts O3 to O2
Depletes the ozone layer in the Earth's Atmosphere
158
UVA Radiation
320-400 nm, not absorbed by ozone layer
| penetrates deep into the skin and contributes to premature aging along with smoking
159
UVB Radiation
```
290-320 nm
MOstly absorbed by the ozone layer
Causes C-T Transition
Causes sunburn
Forms pyrimidine dimers
```
160
UVC Radiation
100-290 nm
| Completely absorbed by ozone layer and atmosphere
161
The level of UV Radiation reaching the earth depends on
```
Cloud coverage,
Time of Day/year
Latitde (Equator has more exposure)
Altitude (higher up, more exposure)
Reflection (Water, Sand, and snow reflect UV light)
```
162
Skin type scale from FDA
1-6
1 and 2 burn rapidly
5&6 have darker skin and do not burn as easily
163
Freckles and skin cancer
Studies show that people with freckles and moles have an increased skin cancer risk
164
Darker skin tones and skin cancer
These patients tend to have more lethal skin cancer because of access to care and health disparities
165
Sunscreen protects by
Absorbing and or reflecting UVA and UVB rays
166
SPF (sun protection Factor)
Relative amount of sunburn protection that a sunscreen can provide
15+ is recommended, covers at 90%, 30 SPF covers 97%
Broad spectrum (UVA and UVB) Protection is recommended
167
There is no such thing as
a healthy suntan
168
In tanning, a person faces
UV radiation as strong or stronger than a midday sun
169
People who tan before age 35
have a 60% increased risk for melanoma
170
What countries outlawed skin tanning?
Brazil 2011
| Austrailia 2015
171
Types of Skin Cancer
Basal Cell
Squamous Cell
Melanoma
172
UVA Damage
Damages via free radical mediated damage
| Water is fragmented generating electron-seeking Reactive Oxygen Species that cause DNA Damage and G-> T Transversion
173
UVB Damage
Conjugated double bonds in the rings of nitrogenous bases of DNA absorb UV Radiation
Causes Cylobutane pyrimidine dimers )(Formed more frequently)
174
Pyrimidine-Pyrimidine Photoproducts
Mimics abasic site (fills in with nothing there)
175
Cyclobutane pyrimidine dimers cause
Bends in the DNA helix and DNA polymerase cannot read the DNA Template
DNA Polymerase skips the misshapen parts and causes a frameshift
176
UV Is carcinogenic to skin because
It doesn't penetrate deeper than skin
177
UV Damaged skin is eliminated by
apoptosis
| familiar to us as peeling after sunburn
178
Mutations in p53 Gene are important in
Squamous cell and basal cell carcinoma and provides an important growth advantage
179
Mutations in what gene are found in 66% of Malignant Melanoma (T->A)
BRAF Gene
180
Mechanisms of Chemical Carcinogens
an electrophilic (Electron-Deficient) form reacts with the nucleophile site in purine and pyrimidine rings of nucleic acids
181
How are Chemical carcinogens activated
Some act directly on DNA
| Others become activated and cancerous via liver processing
182
10 Groups of Carcinogenic Compounds
* Polycyclic aromatic hydrocarbons
* Aromatic amines
* Nitrosamines and Nitrosamides
* Azo dyes
* Hyrazo and azoxy compounds
* Carbamates
* Halogenated compounds
* Natural products
* Inorganic carcinogens
* Miscellaneous compounds (alkylating agents, aldehydes, phenolics)
183
DMBA (7,12-dimethyl benz(a)anthracene)
one of the most potent carcinogens
184
Benzo(a)pyrene (BP)
well known carcinogen in cigarette smoke
185
CYP1
metabolizes BP in BP diol epoxides
| • Cause G → T transversions
186
Aromatic Amines are carcinogenic by
cooking meat formed from heated amino acids and proteins
187
Nitrosamines and Nitrosamides (Carcinogenic)
Found in tobacco
| Formed when preservatives nitrites react with amines in fish and meat during smoking
188
Alkylating agents as a carcinogen
Are able to form intra-Chain and inter-chain cross-links on the DNA Directly
189
Alkylating agents as a carcinogen (Examples)
Melphalan
Methylchorethamine
Chlorambucil
Cytoxan
190
Asbestos
A group of fibrous silicate minerals that were extensively used in building materials
They break down macrophages, bring cytokines and hemokines, causing inflammation (Hallmarks of cancer)
191
Erionite
A Fibrous zeolite mineral formed from volcanic rock
192
Asbestos is associated with
Several lung diseases and associated cancers, mesothelioma
193
Kaposi's Sarcoma
Associated with Herpesvirus (KSHV or HHV8)
194
Hepatiis B and C as a carcinogen
Causes Liver cancer
195
Epstein-Barr Virus as a carcinogen
Associated with Nasopharyngeal Cancers
196
Human T-cell lymphotropic virus type 1(HTLV-1) as a carcinogen
acute T-cell leukemia (ATL)
197
Helicobacter pylori as a carcinogen
stomach ulcers and gastric cancers
198
Salmonella enterica (S. ty) as a carcinogen
Hepatobilliary and gallbladder carcinoma
199
Endogenous Carcinogenic Reactions
Created during cellular metabolism, causing DNA mutations
Errors in DNA Replication
Deamination of Cytosine to Uracil
200
Oxidative respiration and fat metabolism produce _____ that react with DNA and lipids producing oxidized
products (8-oxoguanine)
ROS (Reactive OXygen species)
201
Number of nucleotides in the human genome
6 Billion
202
Error Rate of DNA Polymerase
1 in 6
203
5 Types of DNA Repair systems
* One-step repair
* Nucleotide excision repair (NER)
* Base excision repair
* Mismatch repair
* Recombinational repair
204
One-Step Repair
Direct reversal of DNA Damage
205
Nucleotide Excision Repair
```
• Specific for helix distorting
lesions such as pyrimidine dimers
caused by UVB
• Cuts out 24-32 bases of one
strand with the help of
exonucleases and DNA
polymerase fills the gap
```
206
Disease caused by Nucleotide Excision Repair
Xeroderma pigmentosum (XP)
207
Two Subpathways of the Nucleotide Excision Repair
Global Genome NER
| Transcription-Coupled Repair
208
Global Genome Nucleotide Excision Repair
surveys genome for helix distortion
209
Transcription- Coupled Repair
surveys that damage that interferes with transcription
210
Mismatch Repair
Corrects errors that have escaped editing by polymerase and also repairs insertion and deletion mutations
211
Recognition of mismatch is carried out by what proteins
hMSH2/3
(hMLH1/hPMS1) and hMLH1/hPMS2 are recruited
• Newly synthesized strand with mutation is identified
• Endonucleases and exonucleases remove bases around and including mismatch
• DNA polymerase synthesizes new strand
212
Hereditary non-polyposis colorectal cancer (HNPCC)
```
most common cancer syndrome in humans
Lynch Syndrome
Autosomal dominant mutation disease
80% progress to cancer, increased risk for other cancers
Leads to microsatellite instability
```
213
Recombination Repair
Double-Stranded DNA Breaks
2 Types
Homologous Recombination
Non-Homologous End Joining
214
Homogous Recombinaton
Depends on presence of sister chromatids
215
Non-Homologous End Joining
Does not depend on presence of sister chromatids and can lead to frame shift mutation and chromosomal translocation
216
ATM Kinase
ataxia telangiectasis mutated
| Activated by a double-stranded break
217
RAD50/MRE11/NBS1 complex uses
5’ → 3’
| exonuclease activity to create single-stranded 3’ ends
218
BRCA 1/2 aids in the nuclear transport of
RAD51
219
RAD52 facilitates
RAD51 binding to these exposed ends to form a nucleoprotein filament
220
RAD51 can
exchange a homologous sequence from a single strand within a double-strand molecule with a singlestranded sequence
221
Resolvace
restors the junctions formed as a result of
| homologous recombination, called Holliday junctions
222
Holliday Junctions
cross-shaped structure that forms during the process of genetic recombination, when two double-stranded DNA molecules become separated into four strands in order to exchange segments of genetic information.
223
Diseases associated with Recombination Repair
Burkitt's Lymphoma
| Acute Myeloid Leukemia
224
Ataxia telangiectasis
an inherited syndrome where by patients have a mutation in the ATM kinase
• Patients are sensitive to X-rays and have an increased risk of lymphoma
225
Germline Mutations in BRCA 1 and BRCA 2 genes
Give rise to an increased risk of breast and ovarian cancer
| Those who developed cancer show that they acquired a second mutation later in life
226
BRCA1 and BRCA2 act as
Tumor Suppressor Genes
227
Germline Mutations
Occur in reproductive cells and pass mutations on to progeny or affect gamete viability
228
Therapeutic Strategies of chemotherapy
Apoptosis, killing cells by inducing extensive DNA damage
Inhibiting DNA metabolism by blocking DNA synthesis in rapidly dividing cancer cells
Other drugs interfere with mechanisms of cell division
229
DNA Adduct
Form of DNA Damage caused by covalent attachment of a chemical moiety to DNA
A segment of DNA bound to a cancer-causing chemical, can lead to carcinogenesis and can be used as a biomarker of exposure
230
Chlorambucil (DRUG)
A member of the nitrogen mustard family of drugs
Targets N7 position of Guanine forming intra strand and inter-strand cross-linking, preventing the separation of DNA strands and interfering with replication
231
Clyclophosphamide (DRUG)
Requires metabolic activation within the body
| Also used for rheumatoid arthritis
232
Cyclophosphamide method of action
Oxidases in the live produce an aldehyde form that decomposes to yield an active form called phosohamide mustard
233
Cisplatin and Carboplatin
Platinum-Based drugs that form covalent bonds via platinum atom
Binds to N7 position of Ganine and adenine in its DNA Target
the GG, AG and GXG Adducts comprise over 90% of the total resulting in apoptosis
234
Cisplatin and carboplatin work well on what type of cancer?
Ovarian Cancer
235
Cisplatin and Carboplatin side effect
Causes irreversible kidney damage
236
Antibmetabolites
Structurally simiar to nitrogen bases of DNA and inhibits the role and nucleic acid sequences
237
Fluorideoxyuridylate (Fdump) and Methotraxate
F-DUmp competes with DUMP afor the catalytic site of thymidylate synthase, the enxyme that produces thrymidylase (dMTP), inactivating the enzymethrough covalent modification
238
Methotrexate
A competetive inhibitor of dihydrofolate reductase (DHFR) required in thymidylate synthase reaction
239
Doxoribucin
A fungal anthracycline antibiotic that inhibits topoisomerase II enzyme (Used in colon cancer)
240
Topoisomerase II Enzyme
Releases torsional stress during DNA replication, by trapping single-stranded and double-stranded DNA intermediates
241
Doxorubicin Side effects
Cardiac damage is the most severe side effect
242
Doxorubicin uses
Treating solid tumors (Breast or lung)
243
Vincristine and Vinblastine
Madagascar periwinkle plant alkaloids
| Binds to tubulin and prevents microtubule assembly and disrupts mitotic spindle formation during cell division
244
Radiation Therapy
It is used alone or in combination with other therapies
• Ionizing radiation is usually delivered to the tumor by
electron linear accelerators
• Reacts with water inside the cell generating reactive
oxygen species (ROS) that damage DNA and result in
apoptosis
245
Cells deep within the tumor which are farthest from blood vessels will receive______ doses than cells near the blood vessel
Lower
246
Cells within the same tumor can acquire______
| mutations and some can become drug resistant
Different
247
Anticancer drugs impose strong _______ ________and can select cells that are drug resistant
Selection Pressure
248
________ codes for P-glycoprotein (P-gp) which can bind to drugs such as doxorubicin, vinblastin and taxol and release drug extracellularly
The multiple-drug resistance gene (MDR1)
249
Resistance to methotrexate occurs by
Mutation of Folate Transporters
250
Some cancer cells ______ ____ ________ that are
| responsible for transporting drugs into the cell rendering them non-functional
mutate the transporters
251
DHFR (Dihydrofolate reductase) gene
is amplified in some cancer cells
252
Increased alkyltransferase activity, can give rise to
resistance from alkylating agents
253
Transcription factors
proteins that bind to gene promoters and regulate transcription
254
DNA-Binding Domains
These domains are characteristic protein
conformations that enable a transcription factor
to bind DNA.
▪ It is the conformation of these protein domains
that facilitates binding to DNA
255
DNA Binding Domains
▪ Helix-turn-helix motif
▪ Zinc finger motif
▪ Leucine zipper motif
▪ Helix-loop-helix motif
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Helix-turn-helix motif
The amino acid side-chains of the alpha helix
portions of the helix-turn-helix motif lie in the major
groove of the DNA helix and hydrogen bond to
specific DNA base pairs
257
Zinc finger motif
It is approximately 30 amino acids long and is
configured around a zinc atom that links two cysteines
and two histidines or two cysteines and two cysteines.
▪ It consists of a simple ββα fold and side-chains of
specific amino acids recognize a specific DNA
sequence.
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Transcriptional activation domains
function by binding to other components of the transcriptional apparatus in order to inducetranscription by RNA polymerase
259
Dimerization domains
Some transcription factors work in pairs ("dimer") and require a dimerization domain which facilitates protein-protein interactions between the two molecules
260
Ligand-binding domains
Some transcription factors
only function upon binding of a ligand and therefore
require a ligand-binding domain
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The activity of a transcription factor can be
| regulated by
Several Means
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EMSA – Electrophoretic Mobility Shift Assay
The EMSA s used to study protein: DNA complexes
and interactions
Protein:DNA complexes migrate more slowly than unbound linear DNA on a non-denaturing gel, causing
a "shift."
263
DNase I Footprinting
▪ A method for determining the location of a protein binding site
▪ It involves endonuclease treatment of an end labeled DNA fragment bound to a protein.
▪ Limited digestion yields fragments terminating everywhere except in the footprint region, which is protected from digestion.
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AP-1 Transcription Factor Family
AP-1 is itself activated in response to specific signals such as growth factors, ROS, and radiation
▪ AP-1 binds either to the 12-0-tetradecanoylphorbol13-acetate (TPA) response element or the cAMPresponse element in the promoter region of their
target genes.
▪ That interaction controls the processes of growth, differentiation, and death, and plays a role in carcinogenesis
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The AP-1 transcription factor is actually composed of ____ components and can be produced by dimers of proteins from the Jun (Jun, Jun B and Jun D) and Fos families (Fos, Fos B, FRAl, and FRA2)
TWO
266
Steroid hormones are
lipid-soluble signaling molecules that exert their effects by regulating the transcription of sets of genes via specific receptors.
▪ Can result in Self-sufficiency in growth signals
267
The simplest or primary level of organization of chromatin is the wrapping of DNA around a protein "spool" and is referred to as the "____ __ _ _____" array
Beads on a string
268
Nucleosome contains
147 base pairs (bp) of DNA wrapped 1.7 times around a core of histone proteins
269
The histone core
an octomer of histones containing two copies of
| histones H2A, H2B, H3, and H4
270
Each histone contains domains for
▪ histone-histone
▪ histone-DNA interactions
▪ NH2-terminal lysine-rich
▪ COOH-terminal "tail" domains
271
How do histones attract the DNA to wrap around them?
THe net positive charge of the histones attracts the negatively-charged DNA
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Histone types (5)
H1, H2A, H2B, H3, H4
273
Every protein has two ends:
C-Terminus (Carboxyl Side)
| N-Terminus (Amine Side)
274
HIstone Modification
Acetylation
Methylation
Phosphorylation
275
Histone acetyltransferases (HATs)
catalyze the transfer of an acetyl group from acetyl coenzyme A (UNWIND DNA)
276
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HDACS
histone deacetylases (HDACs)
```
perform the antagonistic action of removing the acetyl group. Histone acetylation plays an important role in the modulation of chromatin condensation and transcriptional regulation (WIND TIGHTLY)
277
Epigenetic Changes
reversible changes in DNA and do not alter the DNA sequence
No Nucleotide changes
They affect gene expression to turn them on and off
278
Epigenetics
The study of how your behaviors and environment can cause changes that affect the way your genes work
Heritable information that is encoded by modification of the genome and chromatin components
279
2 Types of Epigenetic Mechanisms
Histone modification
| DNA Methylation
280
Epigenetic changes are influenced by
How DNA gets wrapped around histones making genes readable and unreadable
Instructions on how to differentiate and develop
281
Histone Modification
Covalent post-translational modifications (PTM) to histone proteins
These can alter gene expression by altering chromatin structure
282
Histone protein are subject to diverse post-translational modifications including
Acetylation
Methylation
Phosphorylation
Ubuquination
283
Histone code hypothesis
predicts that the
pattern of these multiple histone modifications
helps to specify the components and activity of the
transcription regulatory molecular machinery
284
Acetylation
Addition of an acetyl group to histones from Acetyl Co-A (from the Krebs Cycle)
285
Acetylation plays an important role in the following
```
Transcription
DNA Replication and Repair
Cell cycle Progression
Differentiation
Gene Silencing
```
286
EP300
Codes for a HAT, and has been found to be mutated with epithelial cancers
287
Acute Promyelotic Leukemia (APL)
associated with aberrant recruitment of HDACS (tightening DNA)
288
APL Genetic info
Translocation 15:17
289
Methylation or demethylation Can
Turn a gene on or off
| Causing repression or activation of genes
290
DNA Methyl Transferases (DNMTs)
Mediate the covalent addition of a methyl group
291
Hypermethylation of the estrogen receptor
a gene promoter was observed in 3/4 of human ovarian cell lines that lacked estrogen receptor protein
292
Retinoblastoma (Rb) gene
A tumor suppressor gene that is hypermethylated in several cancers
293
Breast cancer Susceptibility Gene (BRCA1) is mutated in what manner?
Recessive
294
What type of DNA repair mechanism results in BRCA1 mutation
Recombination Repair RAD51
295
Phosphorylation
a transient histone modification induced by extracellular signals such as DNA damage
296
DNA Phosphorylation is associated with various biological processes including
DNA Damage Repsonse
DAN Repair
Apoptosis
Chromatin Compaction
297
Proteasomes
part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. Proteins are tagged for degradation with a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases
298
Misregulated epigenetic silencing
| Role in cancer
Can cause inactivation of large groups of genes
| Can result in genome-wide alterations and genomic instability
299
Semiconservative DNA replication
two copies of the original DNA molecule are produced, each copy conserving (replicating) the information from one half of the original DNA molecule
300
DNA is copied by DNA polymerase in what direction?
In the 5' → 3' direction
301
DNA Replication is initiated by
an RNA primer
302
The leading strand is synthesized
Continuously
303
The lagging strand is synthesized
Discontinuously
| RNA primers are removed and Okazaki fragments joined by a DNA polymerase and DNA ligase
304
The 3' end of the parental chromosomal DNA
is not replicated and thus chromosomes progressively erode during each round of replication
305
When the chromosomes reach a threshold length, cells enter a stable and irreversible state of growth arrest called
cellular senescence
306
If cells bypass the cellular senescense stage because of mutation and telomeres become critically short
chromosomal instability results and apoptosis is induced
307
Telomeres are composed of
several thousand repeats of the sequence TTAGGG bound by a set of associated proteins called the shelterin complex, which functions to control telomere
length and protect the chromosomal ends
308
Shelterin Complex
a six-subunit protein complex (comprising TRF1, TRF2, POT1, TPP1, TIN2 and Rap1) that associates specifically with mammalian telomeres and allows cells to distinguish the natural ends of chromosomes from sites of DNA damage
309
Telomeres shorten by___ ____ with each
round of DNA replication owing to the limits of
DNA polymerases during DNA
100-200 bases
310
A ribonucleoprotein containing human telomerase reverse transcriptase activity (hTERT) and a
human telomerase RNA (hTR) maintain telomere length in certain cell types, such as stem cells
Telomerase
311
The hTERT contains
11 complementary base pairs to the TTAGGG repeats and acts as a template for the reverse transcriptase to add new repeats to telomeric DNA on the 3' ends of chromosomes
312
Telomere Nucleotide Sequence
TTAGGG
