Exam 4 Flashcards

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1
Q

cell cycle

A

highly regulated process cells use to decide when and how to divide

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2
Q

why is cell division so tightly regulated?

A

defects in cell cycle regulation cause:
1) mutations (un-fixed errors)
2) cancer (too much proliferation, too little cell death)
3) atrophy (too little proliferation, too much cell death)
4) aneuploidy (too many or too few chromosomes)

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3
Q

major regulators of the animal cell cycle

A

1) secreted growth factors (environmental)
2) DNA integrity (intrinsic)
3) cell volume (intrinsic)
4) cell density (environmental)

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4
Q

major regulators of the animal cell cycle:
secreted growth factors

A

ligand from ER in cell signaling that does not get metabolized;
regulates cell proliferation, migration, survival/apoptosis;
intracellular response of cell that causes some change

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5
Q

major regulators of the animal cell cycle:
DNA integrity

A

lesions (from intrinsic or extrinsic carcinogens or errors in DNA replication) block replication progress and impair chromosome separation

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6
Q

major regulators of the animal cell cycle:
cell volume

A

cells know how big they are to help maintain cellular tissue integrity;
cell cycle and growth are interdependent (cells add constant volume each cell cycle, independent of initial size)

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7
Q

major regulators of the animal cell cycle:
cell density

A

cells are mindful of their neighbors (CAMs help recognize each other and environment);
contact inhibition of proliferation results in mitotic arrest and promotes differentiation

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8
Q

euk cell cycle phases

A

interphase (G1, S, G2) and M phase (prophase, metaphase, anaphase, telophase)

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9
Q

interphase

A

prep stages: cell grows, duplicates chromosomes, synthesizes machinery for replication;
every stage checks for DNA integrity

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10
Q

interphase:
G1

A

increase in cell volume, RNA and ribosome synthesis, protein synthesis for DNA replication

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11
Q

interphase:
S

A

chromosome and centrosome duplication, histone synthesis

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12
Q

interphase:
G2

A

protein synthesis for M phase

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13
Q

M phase:
prophase

A

centrosomes migrate to opposite poles, chromosome condensation, mitotic spindle formation, microtubule polymerization, NE breaks down

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14
Q

M phase:
metaphase

A

kinetochore alignment and attachment to chromosomes, tension builds across spindle

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15
Q

M phase:
anaphase

A

chromosome separation to two poles

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16
Q

M phase:
telophase

A

nuclear membrane reforms around both, cytokinesis begins (ends by G1), actin-myosin contractile ring

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17
Q

typical human cell division

A

every 24 ish hours, 95 % of cell cycle is spend in interphase;
budding yeast division takes 90 minutes, cells in early embryo take 30 minutes (skip growth stages)

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18
Q

G0

A

life outside the cell cycle where cells are not dividing or preparing to divide;
three distinct cell types

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19
Q

cell types in G0

A

1) quiescent
2) senescent
3) differentiated

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20
Q

cell types in G0:
quiescent

A

reversible G0, programmed event;
cells can be stimulated to re-enter the cell cycle

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21
Q

cell types in G0:
senescent

A

irreversible G0, reactive event (DNA damage, telomere shortening, growth factors);
cells cannot be stimulated to re-enter the cell cycle (except tumor cells);
discovered by Hayflick and Moorhead

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22
Q

Hayflick limit

A

the number of times a normal, differentiated, somatic cell will divide before stopping

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23
Q

cell types in G0:
differentiated

A

irreversible G0, programmed event (not damage induced);
cells cannot be stimulated to re-enter the cell cycle (except dedifferentiation or transdifferentiation)

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24
Q

major cell cycle phase-associated checkpoints

A

1) restriction point
2) G1/S
3) G2/M
4) spindle checkpoint
plus lots of DNA damage checkpoints by Chk1 and Chk2 throughout interphase, p53 in G1

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25
Q

cyclin-dependent kinases (CDKs)

A

regulate cell cycle entry and progression by phosphorylating targets;
serine/threonine protein kinases;
inactive until bound by co-activator cyclin proteins

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26
Q

CDKs are in molar excess throughout cell cycle…
how do we make sure CDKs are working on the right targets during the right phase?

A

1) cyclin expression
2) CDK inhibitors
3) inactivating tyrosine phosphorylation

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27
Q

cyclin expression

A

waves of synthesis and degradation through ubiquitination (APC/C ubiquitin ligase targets cyclins for degradation in late M and G1)

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28
Q

cell cycle entry/continuation

A

growth factors and nutrients stimulate entry to cell cycle once they reach a certain level;
1) growth factors activate RTKs and ERK MAPK pathway
2) phosphorylated ERK activates TFs for IEGs (Elk1)
3) expression of SRGs including CycD
4) CycD activates CDK4,6

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29
Q

G1 restriction point

A

the point at which removal of growth factors and nutrients does not stop cell cycle progression (commitment to the cell cycle)

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30
Q

G1 molecular basis of restriction point

A

phosphorylation of Rb by CDK4,6/CycD;
releases repression of E2F family TFs

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31
Q

G1/S transition

A

1) E2F transcription
2) increases CycE expression
3) activates CDK2
*positive feedback: CDK2 phosphorylates Rb more

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32
Q

G1/S transition CDK2/CycE inhibition

A

inhibited early in G1 by p27 and APC/C until…
growth factors decrease p27 synthesis, CDK2/CycE promotes p27 degradation and APC/C inactivation

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33
Q

G1/S transition is promoted by ___

A

high level of CDK2/CycE promotes loading of prereplication complex (with MCM) on origins to prepare for replication in S

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34
Q

S phase events

A

1) increased CycA expression, CycE degradation
2) CDK2/CycA phosphorylates MCM helicase proteins at origin to activate
3) high CDK activity stops re-replication

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35
Q

G2/M transition

A

1) increased CycB expression
2) activates CDK1 in M phase
3) CDK1/CycB (MPF) phosphorylates 1000s of targets including Aurora A and B and polo-like kinases (positive feedback loop)
4) CDK1/CycB initiates activation of APC/C (inhibited by MCC until chromosomes properly align)

1) CDK1/CycA promotes accumulation of CDK1/CycB in nucleus
2) nuclear envelope breakdown

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36
Q

spindle checkpoint

A

ensures all chromosomes are properly attached to microtubules at their kinetochores during metaphase;
APC/C inhibited until proper attachment

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37
Q

mitotic exit

A

1) APC/C activation
2) degradation of CycB
3) inactivation of CDK1
4) promotes mitotic exit and cytokinesis

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38
Q

Aurora A and polo mutants

A

have mono-polar spindle and do not undergo cytokinesis

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39
Q

Aurora B mutants

A

have partial condensation and disrupted spindle attachment

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40
Q

prophase spindle assembly

A

1) Aurora A and polo phosphorylation
2) accumulation of pericentriolar material
3) microtubule anchoring proteins hold - ends
4) y-tubulin initiates microtubule polymerization

1) astral microtubules attach to cell cortex
2) centrosomes migrate to opposite poles

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41
Q

prophase NEB (nuclear envelope breakdown)

A

1) CDK1/CycB phosphorylation
2) NPC disassembly and lamina depolymerization (weakens NE)
3) microtubule polymerization tears and stretches NE
4) NE fragments into vesicles

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42
Q

prophase chromosome condensation

A

1) cohesin rings applied to sister chromatids in S phase
2) CDK1/CycB and Aurora B phosphorylation on chromatin proteins
3) condensins bind and package chromosomes into loops
4) NEB removes attachments to chromosomes (like springs poised to condense)

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43
Q

prometaphase

A

1) + end of kinetochore microtubules attach to kinetochore proteins on chromosomes
2) motor proteins (kinesin and dynein) and MT polymerization/depolymerization initiate the shuffle

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44
Q

microtubule orientation to midline and centrosome

A

+ end at midline
- end at centrosome

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45
Q

metaphase

A

1) spindle assembly checkpoint
2) formation of MCC complex inhibits APC/C

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46
Q

metaphase spindle assembly checkpoint

A

monitors the attachment of chromosomes to the spindle, looks for unattached kinetochores and improper tension

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47
Q

metaphase improper assembly

A

Aurora B turns over improper attachments (phosphorylates kinetochore proteins) and promotes assembly of MCC complex

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48
Q

anaphase transition

A

1) proper attachments decrease MCC complex formation which activates APC/C
2) chromosomes separate and move to centrosomes at opposite poles

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49
Q

anaphase transition APC/C activation

A

1) degradation of CycB
2) inactivates CDK1

1) degrades securin
2) releases separase
3) degradation of cohesin

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50
Q

telophase

A

1) nucleus reforms
2) cytokinesis begins

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51
Q

telophase nucleus reformation

A

1) vesicles bind to chromosomes
2) vesicles fuse
3) reformation of nuclear lamina
4) chromsome decondensation
5) NPC reestablished
6) nuclear proteins imported

52
Q

telophase cytokinesis begins

A

animal cells divide cytoplasm by ingression of cleavage furrow midway between separated chromosomes;
polo-like kinases

53
Q

telophase cytokinesis polo-like kinases

A

play major role in localization of contractile ring and initial ingression of spindle;
localizes at the overlap of the interpolar microtubules and promotes tightening of actin-myosin contractile ring

54
Q

ATR and ATM

A

protein kinases that recognize damaged DNA throughout interphase
1) activate signaling pathway
2) cell cycle arrest and DNA repair mechanisms
3) cycle progress OR cell death

55
Q

ATR activated by

A

1) ss breaks or unreplicated DNA
2) ATR activation
3) phosphorylation (activation) of Chk1

56
Q

ATM activated by

A

1) ds breaks
2) ATM activation
3) phosphorylation (activation) of Chk2

57
Q

Chk1 and Chk2

A

protein kinases that inhibit Cdc25
1) Chk1 or Chk2 activation
2) phosphorylation of Cdc25 phosphatases
3) inhibits or promotes degradation of Cdc25

58
Q

Cdc25

A

cell cycle inhibitor that normally removes inhibitory phosphorylation on Cdk1 and Cdk2

59
Q

ATM/Chk2 pathway also activates ___

A

p53

60
Q

p53

A

TF in activated form that regulates gene expression
1) ds break
2) ATM
3) Chk2
4) phosphorylation of p53
5) stabilization of p53
6) formation of active p53 tetramers
7) acts as TF at p53-response element sequences in the regulatory region of target genes

61
Q

p53 targets

A

100s of targets including p21

62
Q

p21

A

CDK inhibitor (CDKi)
1) inhibits Cdk1 and Cdk2
2) cell cycle arrest

63
Q

less differentiated cell types

A

1) stem cells
2) cancer cells

64
Q

stem cells

A

unspecialized cells that differentiate into specialized cells
1) self renewing
2) potency

65
Q

cancer cells

A

include malignant tumors made of anaplastic cells

66
Q

malignant

A

fast growing, metastatic (spreading from primary tumor site)

67
Q

anaplasia

A

lack differentiation and features of origin tissue (take a step back in differentiation from surrounding cells)

68
Q

potency

A

potential to differentiate
1) totipotent
2) pluripotent
3) multipotent
4) unipotent
5) differentiated

69
Q

totipotent

A

can become every cell type; not in adult;
fertilized egg/zygote

70
Q

pluripotent

A

can become every cell type except placenta; not in adult;
ex. inner cell mass (ICM) of embryo, iPSCs

71
Q

multipotent

A

can become limited (multiple) cell types;
often lineage/cell type specific/restricted;
ex. neural, hematopoietic, intestinal stem cells

72
Q

unipotent

A

can become only one cell type; aka progenitor cells;
ex. satellite cells in muscle

73
Q

differentiated

A

fully specialized, non-stem cells; some quiescent;
ex. fibroblasts, endothelial, liver cells

74
Q

ways to replace dead/dying cells

A

1) proliferation of differentiated cells
2) proliferation of stem cells

75
Q

proliferation of differentiated cells

A

fully specialized, quiescent (G0) cells can be stimulated to reenter cell cycle (secreted growth factors);
1) fibroblasts
2) endothelial cells

76
Q

proliferation of differentiated cells:
fibroblasts

A

rapidly proliferate in response to PDGF (platelet-derived growth factor); secrete new ECM and coordinate contraction at wound site

77
Q

proliferation of differentiated cells:
endothelial cells

A

recruited by cells secreting VEGF (vascular endothelial growth factor; proliferation forms new blood vessels to support tissue needs (angiogenesis)

78
Q

proliferation of stem cells

A

less specialized, sometimes quiescent (G0) cells that proliferate throughout their lifetime in most tissues; proliferation can be self-renewing and/or make differentiated cells;
asymmetric vs symmetric division;
ex. hematopoietic, intestinal, satellite stem cells

79
Q

proliferation of stem cells:
asymmetric division

A

produces one stem daughter cell and one non-stem daughter cell; so we don’t run out of stem cells;
non-stem daughter cells vs transit-amplifying cells

80
Q

proliferation of stem cells:
asymmetric divsion - non-stem daughter cells

A

proliferate into transit-amplifying cells

81
Q

proliferation of stem cells:
asymmetric division - transit-amplifying cells

A

undifferentiated intermediates that become differentiated cells

82
Q

proliferation of stem cells:
symmetric division

A

produces two stem daughter cells OR two non-stem daughter cells;
ex. adult neural stem cells -> two stem daughter cells;
ex. adult intestinal stem cells -> two non-stem daughter cells

83
Q

proliferation of stem cells:
hematopoietic stem cells

A

in marrow replenish blood cells (fully differentiated blood cells do not divide)

84
Q

proliferation of stem cells:
intestinal stem cells

A

slowly, but continuously divide in the bottom of the intestinal crypts;
fully differentiated surface epithelial cells apoptose and shed into digestive tract

85
Q

proliferation of stem cells:
satellite stem cells

A

re-enter cell cycle to form new muscle fibers (unipotent);
normally quiescent, but injury/exercise-induced proliferation

86
Q

examples of apoptosis

A

1) removing tissue in development (larval, webbed limbs, neuronal pruning)
2) adulthood tissue homeostasis and healthy cell turnover
3) injury (eliminating DNA damaged cells and promoting healthy cell proliferation at wound)
4) insult (killing virus infected cells

87
Q

apoptosis looks like:

A

regulated event (peaceful)
1) cell shrinkage, DNA fragmentation, nuclear fragmentation, plasma membrane blebbing, cell fragmentation
2) rearrangement of PM (phosphatidylserine to outer leaflet)
3) recognized by phagocytic cells that engulf

88
Q

necrosis looks like:

A

EXPLOSION (usually because of acute injury) (neighborhood disturbance)
1) swelling, rupture of membranes
2) release of contents into extracellular space
3) triggers inflammatory response

89
Q

caspase

A

proteases (cleave proteins) that execute apoptotic events;
c = cysteine at active sites;
asp = cleave after aspartic acid

90
Q

caspase targets

A

cleave 100s of target proteins
1) DNase inhibitor -> DNA fragmentation by DNase
2) nuclear lamins -> nuclear fragmentation
3) cytoskeletal proteins -> PM blebbing/cell fragmentation
4) scramblase -> phosphatidylserine translocation

91
Q

caspase activation

A

1) synthesized as inactive precursors, kept at bay in normal cells
2) pro-apoptotic signals start bumpin
3) initiator caspases are activated
4) effector caspases are cleaved/activated by initiators
5) activated effectors cleave target proteins
6) apoptosis yaaaaaay

92
Q

initiator caspases

A

caspase-8, 9, 10

93
Q

effector caspases

A

caspase-3, 7

94
Q

cell signaling pathways that control apoptosis:

A

1) intrinsic (mitochondrial/Bcl-2) pathway
2) extrinsic (receptor-mediated) pathway

95
Q

intrinsic (mitochondrial/Bcl-2) pathway

A

activated by internal stress, regulated by Bcl-2 family proteins (3 types):
1) pro-survival
2) pro-apoptotic
3) effectors (Bax, Bac)

96
Q

intrinsic (mitochondrial/Bcl-2) pathway:
pro-survival Bcl-2 proteins

A

binded to effector to prevent effector activation in normal cells

97
Q

intrinsic (mitochondrial/Bcl-2) pathway:
pro-apoptotic Bcl-2 proteins

A

downstream of death signal bind to pro-survival protein to release effector and promote effector activation

98
Q

intrinsic (mitochondrial/Bcl-2) pathway:
effector Bcl-2 proteins and activation of apoptosis

A

promote caspase activation (apoptosis)
1) oligomerize to poke holes in mito membrane
2) cyt c leaks into cytoplasm
3) cyt c binds to Apaf-1 to form apoptosome
4) apoptosome activates caspase-9 initiator
5) caspase-9 activates caspase-3 effector
6) apoptosis yaaaaaaaay

99
Q

intrinsic (mitochondrial/Bcl-2) pathway:
p53 with Bcl-2 effectors

A

1) DNA damage
2) ATM/Chk2
3) p53
4) cell cycle and DNA repair
5) OR if can’t repair, p53 activates pro-apoptotic Bcl-2 proteins
6) effector Bcl-2 activation
7) apoptosis yaaaaaaay

100
Q

extrinsic (receptor-mediated) pathway

A

activated by external secreted ligands binding to death domain (DD) on tumor necrosis factor (TNF) family receptors

101
Q

extrinsic (receptor-mediated) pathway:
tumor necrosis factor (TNF)

A

subset of TNF family receptors have a death domain (DD)

102
Q

extrinsic (receptor-mediated) pathway:
death domain (DD)

A

cytoplasmic domain on many proteins (not just TNF) that is a platform for self-assembly of the receptor, adaptor proteins, and caspases;
promotes activation of apoptotic caspases and kinases

103
Q

extrinsic (receptor-mediated) pathway:
activation of apoptosis

A

1) TNF ligand
2) TNF family receptor binds
3) adaptor protein assembles on DD
4) initiator caspase-8 or 10 binds adaptor protein
5) activation of caspase-8 or 10
6) activation of effector caspases (also activation of intrinsic pathway by Bid)
7) apoptosis yaaaaaaaaay

104
Q

neoplasm

A

abnormal growth of cells in any part of the body;
uncoordinated with growth of surrounding tissue;
irreversible growth due to accumulated genetic changes;
can be benign (noncancerous) or malignant (cancerous)

105
Q

malignant neoplasm

A

cancerous;
abnormal borders;
less differentiated than origin tissue (anaplastic);
microscopically disorganized (pleomorphic, DNA, mitoses);
evidence of metastasis

106
Q

malignant neoplasm:
anaplastic

A

so poorly differentiated they lack specific features

107
Q

malignant neoplasm:
pleomorphic

A

variation in nuclear and cell size

108
Q

malignant neoplasm:
metastasis

A

spread of tumor through blood, lymph, to body cavities, or directly to adjacent organs;
seed and soil theory

109
Q

malignant neoplasm:
metastasis - seed and soil theory

A

metastases are not random, organ-specific metastasis is because of molecular compatibility between metastatic tumor cell “seed” and secondary tissue “soil”

110
Q

benign neoplasm

A

noncancerous;
smooth, distinct borders;
microscopically organized (similar sizes, shapes, mitoses, DNA content);
often well differentiated, resembles origin tissue;
non-invasive, lack metastasis;
some benign tumors can undergo malignant transformations

111
Q

cancer cell features in vitro that contribute to their deadly, invasive properties in vivo

A

1) loss of density-dependent and contact inhibition
2) autocrine growth stimulation
3) less adhesive to adjacent cells and ECM
4) evade apoptosis

112
Q

cancer cell features:
loss of density-dependent and contact inhibition

A

just grow all over each other

113
Q

cancer cell features:
autocrine growth stimulation

A

can stimulate own growth, send and receive their own growth factors (what a baller move haha)

114
Q

cancer cell features:
less adhesive

A

to adjacent cells and ECM;
float around, don’t stick to surface receptors

115
Q

carcinogens

A

cause cancer by changing cells genome (directly or indirectly);
UV radiation, N-nitrosamines, aflatoxin, bacteria, viruses

116
Q

driver mutations

A

cancer cell mutations that increase cell’s fitness (ability to survive and reproduce) compared to those around it
1) proto-oncogenes
2) tumor suppressors

117
Q

driver mutations:
proto-oncogenes

A

normally growth “accelerators”, pro-survival factors;
activating mutations or over expressed (activation -> cancer);
mutated proto-oncogenes = oncogenes

118
Q

driver mutations:
tumor suppressors

A

normally growth “brakes”, pro-apoptotic factors/DNA repair machinery;
inactivating mutations or under expressed (inactivation -> cancer)

119
Q

passenger mutations

A

cancer cell mutations that are coincidental to the driver, and confer not fitness change
1) sequence changes
2) epigenetic changes (modifications to expression like methylation)
3) larger structural changes (like aneuploidy, copy-number variations)

120
Q

tumorigenesis

A

an evolutionary process
1) the founder
2) clonal expansion
3) genetic diversification
4) subclonal mutations
5) clonal selection

121
Q

tumorigenesis:
the founder

A

a few, or even a single cell acquires driver mutation(s) that enable expansion

122
Q

tumorigenesis:
clonal expansion

A

proliferation of founder gives rise to clones with the original driver mutation(s)

123
Q

tumorigenesis:
genetic diversification

A

mutations occurs as clones expand

124
Q

tumorigenesis:
subclonal mutations

A

some may be driver mutations

125
Q

tumorigenesis:
clonal selection

A

genetically distinct subclonal populations compete within the tumor, heterogeneity