Toxicology Exam 4 Flashcards
cancer
malignancy/malignant neoplasms
carcinogen
complete carcinogen
procarcinogen
mutagen
tumor promoter
proto oncogene
oncogene
tumor suppressor gene
cell proliferation
cancer: Disease of abnormal cell proliferation
malignancy/malignant neoplasms: Uncontrolled cell division of abnormal cells
Invasion of nearby tissues (cancerous growth)
carcinogen: Process by which normal cells become malignant - Xenobiotics that cause cancer in mammals
complete carcinogen: Xenobiotics that don’t require biometabolism
procarcinogen: Xenobiotics that require biotransformation
mutagen: an agent, such as radiation or a chemical substance, which causes genetic mutation
tumor promoter: Xenobiotics that facilitate carcinogenesis. Not genotoxic. Stimulate proliferation. Promote entrance into cell cycle (G0 to G1/S/G2/M)
proto oncogene: Highly conserved genes that normal control growth. Normal development: expansion of tissues. Maintenance of tissue (e.g., GI tract, hair growth bone marrow)
Regeneration/repair of tissues following injury.
Stimulate progression of cells through the cell cycle. Expression is normally transient and tightly regulated. Genetic damage (e.g., mutations) to proto-oncogenes is dominant not recessive. Alteration of only one allele is necessary.Give rise to oncogenes.
oncogene: Derived from mutated proto-oncogene or virus pathogens. Genes capable of transforming cells into malignant
growth. Oncogenic proteins are continuously (constitutively) active forms of proto-oncogenic protein. Virally transmitted genes.
tumor suppressor gene: Genes that produce proteins that inhibit cell proliferation and/or survival (e.g., signal apoptosis)
* Retinoblastoma (Rb)
* P53
Cell proliferation: is necessary for normal tissue development and maintenance over the lifespan.
Carcinogen vs. mutagen
Not all carcinogens are mutagens
- Only about 70% carcinogens are estimated to be mutagens.
- Some xenobiotic carcinogens do not directly cause DNA mutations.
* Modify methylation status of DNA/histones (i.e., epigenetic mechanisms)
* Alter DNA repair or cell death mechanisms
* Promote clonal expansion of cells with pre-existing mutations (i.e., tumor promoters)
Compare oncogenes with tumor suppressor genes
Proto-oncogenes vs tumor suppressor
Tumor promoters(not considered carcinogens, a chemical that causes proliferation, has to be some damage to DNA) (can facilitate not alter genome only cause synthesis of genome so anything damaged in genome if not repaired then p53 will get activated, p53 can get it to die) like protein kinase c (ca can activatie), stimulate proliferation and are bad if we have alterations in the genome that aren’t fixed so not damaged anymore, the two hit models.
Proto-oncogenes
- Promote cell proliferation normally
- Single mutated allele is sufficient to cause cancer
- One non-mutant allele can function normally
- Function of mutated allele is dominant over normal allele to cause malignant cell growth
- Directly promotes malignant cell growth
Oncogenes: Dominant single mutational
event – genotoxic xenobiotics could be
complete carcinogens
Tumor suppressor genes
- Suppress cell proliferation normally
- Both alleles must be mutated to cause cancer
- Single mutated allele is insufficient due to function of normal allele
- Mutation of both alleles removes suppression on cell proliferation
- Indirectly promotes malignant cell growth
Tumor suppressor genes: often recessive requiring two mutational events – genotoxic xenobiotics could be complete carcinogens with multiple exposures or high doses
Somatic cells: genetic damage
Somatic cells:
* All cells that are not destined to become germline (sex) cells
* Genetic alterations occurs after conception (acquired damage)
* These give rise to acquired cancer
* Genetic alterations are not heritable (passed to offspring)
Germline cells (gametes, reproductive/sex cells): genetic damage
Germline cells (gametes, reproductive/sex cells):
* Cells that come together at conception or fertilization
* Ovum (female egg cells) and sperm (male
counterpart)
* Genetic/epigenetic damage occurs prior to
conception
* Genetic damage is heritable (Inherited cancer)
Two hit hypothesis of carcinogenesis and features of each of the three stages
Three stages
* Stage 1: Initiation (first hit)
- Carcinogen exposure (maybe just one time)
- Genotoxic/non-genotoxic genetic alteration
- Favors proliferation over apoptosis
- May be reversible initially (DNA repair)
- Irreversible upon DNA synthesis (mutation becomes
fixed into genome)
- Stage 2: Promotion
- Tumor promoters
- Clonal expansion (proliferation) of initiated cells establishes (fixes) DNA mutation in genome
- Mutation/genotoxicity is not required
- Halted upon removal of growth stimulus (e.g., tumor promoting xenobiotic)
- Can result in benign tumor growth (e.g., papilloma)
Stage 2 tumor promoter - anything that cause proliferation - Stage 3: Progression (second hit)
- Additional genetic alteration (second hit)
- Genetic instability of mutated cell
- Malignancy established
Protognee one allele to mutate - no tumor promotion or second
Protognee stimulate proliferation → mutate portogone that siutmate profelration
One allele to stimulate Tumor promotors
Tummor suppeors both allele
Two hit model - one hit that doesn’t cause carcinogens like tumor suppressor but if you two hits get tumor promoter it causes an expansion) not always needed to hits like proto oncogenes - example is tumor suppressor gene like restsonabloms - one hit allele
Proliferation - p53 will affect dna and then instability of genome - mutation in p53 which is tumor suppressor opens up the possibility of mutagens getting incorporated.
Tumor suppressor genes are received - both genes
Damage can be tumor promoter
Know the acquired capabilities view of carcinogenesis and eight features common to malignant growths.
Proposes that all cancers acquire the same set of functional capabilities
Key enabling characteristics: genomic instability and inflammation
Eight acquired characteristics common to malignant growths:
1) Insensitivity to antigrowth signals (e.g., contact inhibition)
2) Self-sufficiency of growth (i.e., without growth factor stimulation)
4) Limitless replicative potential - immortal
5) Resistant to apoptosis (i.e., increase cell survival)
5) Increased invasive growth and spread (metastasis)
6) Sustained angiogenesis (new blood vessels)
7) Altered energy metabolism
8) Evade immune destruction
Cancer mutations
Ras proto-oncogene
Retinoblastoma (Rb) tumor suppressor gene
P53 tumor suppressor gene
Ras proto-oncogene mutation
- Ras is a G protein like Gs, Gi, and Gq of G protein coupled receptors (recall Pertussis/Cholera toxins)
- Ras acts as receptor for GTP: it is activated by GTP binding
- Ras links growth factors to intracellular cell cycle
- It is activated by growth factor receptors like EGFR
- GTPase activity hydrolysis of GTP to GDP by Ras
Ras proto-oncogene: regulation of normal function
* Guanine nucleotide exchange factor (GEF): Rasassociated protein that promotes exchange of GDP for GTP (activation of Ras)
* GAP (GTPase-activating protein): Ras-associated protein stimulates GTPase activity of Ras (inactivation of Ras)
- GTP exchange factor - G protein activating protein activates the gtpase ras - exchange (GTP to GDP)
Gtapse to hydrolyze to go back to inactive form
Direct and indirect ras
Both active ras to ocognigen from protogene
Muate ras destroys GTP - permanent
GAP
Ras to an oncogene
Direct the ras protein itself loses GTPase function os cant be inactivated
Indirect regulatory proteins
Independent ways to permanently active ras
Two types of mutations that activate Ras function
1)Direct: mutation of Ras GTPase activity (requires
mutation of only one allele)
2)Indirect: mutation of GAP protein (requires
mutation of both alleles
Consequence of mutations in Ras function
* Prevents hydrolysis of GTP to GDP
* Locks Ras in activate state
Xenobiotic mutagens that activate Ras function
* Benzo[a]pyrene (cigarettes)
* Aflatoxin B (microbial protein)
* N-methyl-N-nitrosurea (DNA alkylating agent)
* Benzidine (dye production)
* Ionizing radiation (x-rays)
Tumor suppressor genes
Genes that produce proteins that inhibit cell
proliferation and/or survival (e.g., signal apoptosis)
* Retinoblastoma (Rb)
* P53
Mutations are recessive not dominant
* Heterozygous mutations (one mutant/one wild-type
allele) are not effective
* Require mutation of both alleles
* Two mutational/epigenetic events (hits) required
These are loss of function mutations
Tumor suppressor genes
Retinoblastoma (Rb) normal function + Consequence
Retinoblastoma (Rb) normal function
* Transcriptional repressor protein
* Inhibits E2F-mediated gene transcription
* Blocks cells from entering S phase of the cell cycle
Consequence of mutation in Rb function
* Inactivation of Rb gene removes EF2 repression
allowing cells to enter S phase
* Note: viral oncogene products (e.g., Large T Antigen of SV40 virus) can bind to and inactivate Rb protein function
Tumor suppressor genes
P53 normal function (“Guardian of the Genome)
P53 normal function (“Guardian of the Genome):
* P53 is a transcription factor that is crucial
for checkpoint control in G1 phase of cell
the cycle
* DNA damage causes P53 to arrest cells in
G1 phase of cell cycle
* Arrest allows DNA repair or apoptosis to occur
P53 (“Guardian of the Genome”): signal transduction
* Unphosphorylated P53 protein is unstable (short half-life)
* DNA damage activates ATM protein kinase
* ATM phosphorylates P53 increasing its stability
* Phosphorylated P53 binds to DNA and activates gene transcription
* Increase expression of proteins involved in cell cycle arrest (e.g., p21), DNA repair, and cell death (apoptosis)
P53 (“Guardian of the Genome”): normal regulation
* P53 is inactivated by a natural inhibitory protein, MDM2
Mutations that inactivate P53 function
* Direct: mutation of P53 gene (loss of function)
* In direct: gene amplification of MDM2
Xenobiotics that cause p53 gene mutation
* Benzo[a]pyrene (cigarettes)
* Aflatoxin B (microbial protein)
* Ionizing radiation
Protein to regulate is MDM2 until turn off
Indirect the more MDM2 the better at superssing p53 but too much then p53 will be suppressed (if you want cancer) - MDM2 is bad
One is they stimulate proliferation and allows mustagen into the genome
Two they create more cells of that mutation to second hit
Cells lose contact inhibition
Genomic instability means that the cell has mechinsima to fix dna damage is happening all the time depending where the cell like the skin is under attack by UV radiation so skin has potioanl of mutations going into the genome and if those mutations are not repared then they can be fixed in the genome by proliferation so instability means there is one example alteration in DNA repair and relates to P53 bc it can arrest cell cycle in G1 Phase while the cell repairs the DNA and p53 activated by DNA damage so it can initiate DNA repair mechanisms and fix all of that
Mutation to P53 or damage to DNA repair mechanisms consequence is genomic instability and connects to hit hypothesis and genomic insiatbilty can be incorptretd into the geneom once cell under goes proliferation unless p53 is there to hult and repair but if too much p53 initiate apoptosis
Periods of developmental
* Gametogenesis
* Fertilization
* Embryonic period
* Fetal period
* Postnatal period (further development after birth to puberty)
Gestation
- Gametogenesis: formation of gametes (reproductive cells; egg and sperm) Meiotic cell division to form haploid germ cells (single
copy of chromosomes) - Fertilization: formation of zygote
Conception: gametes fuse forming diploid cell (copies of chromosomes from both parents)
*Gestation includes (Embryonic period + Fetal period) after fertilization and birth
Period between conception and birth
1st trimester: embryonic period
2nd and 3rd trimesters: fetal period
- Postnatal period (further development after birth to puberty): Continued growth, development, and differentiation of
organs (e.g., reproductive organs, central nervous system, muscles). Physiological maturation (e.g., coordination, cognition,
speech, etc.)
Gestation 1st trimester: embryonic period
Three Subdivisions
2nd and 3rd trimesters
Pre-implantation period: 1st week following fertilization
- Characterized by rapid mitotic cell division
- Formation of blastocyst stage of embryo
Post-implantation period: 2nd/3rd weeks
- Blastocyst moves through oviduct and implants in wall of uterus
- Characterized by cell migration and mitotic division
- Gastrulation: formation of three primary germ layers
Organogenesis period: Initiated in 3rd week
- Cell proliferation, migration, cell-cell interactions
- Morphogenic tissue remodeling
- Fundamental elements of most body parts are formed (e.g., limb buds, internal organs)
2nd and 3rd trimesters
* Period of tissue growth, differentiation, physiological
maturation
* Fine structure morphogenesis of tissues
* All organs are grossly recognizable and attain requisite functionality prior to birth
Developmental - General types of alterations
Developmental Overview
Development is a tightly regulated sequence of events
It is characterized by periods of growth and change
General types of alterations
* Structural malformations (e.g., bone)
* Growth retardation (e.g., weight/size)
* Functional/physiological impairments (e.g., cognition)
* Cell and embryonic Death
Teratology
- Teras is the Greek word for monster
- It is the specific study of structural malformations
- Teratogens are xenobiotic that causes structural defects
Critical periods of Toxic events Gametogenesis:
Gametogenesis: Toxic effects prior to conception (fertilization of egg by sperm). Exposure of testis or ovaries. Potentially heritable (trans-generational) alterations in sperm or eggs (mutations; epigenetic alterations)
Infertility: decreased sperm production; increased death of oocytes (note that total female oocytes determined prior to birth)
