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BMS2002 > L22 > Flashcards

L22 Flashcards

(49 cards)

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1
Q

give examples of cells that never divide

A

Mature muscle (cardiac muscle cells)

nerve cells

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2
Q

what cells are Arrested in G0 but can resume proliferation

A

Skin Fibroblast, smooth muscle cells, endothelial cells from blood vessels, epithelial cells (liver, pancreas, kidney, lung, prostate, breast)

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3
Q

what cells need a continuous cell renewal

A

Blood cells, intestinal epithelial cells

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4
Q

what does DNA damage checkpoint inhibit

A

CDK4/6, CDK2, and CDK1/2

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5
Q

what does the replication stress checkpoint inhibit

A

CDK1/2

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6
Q

what does the spindle assembly checkpoint inhibit

A

APC/C

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7
Q

what cells are mutated in cancer

A

Protooncogenes

Tumor suppressors

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8
Q

what are Protooncogenes

A

genes that promote cell growth and proliferation

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9
Q

what are oncogenes

A

mutated protooncogene in cancer

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10
Q

give an example of a protooncogene

A

ABL

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11
Q

give an example of tumor suppressor

A

Rb

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12
Q

Oncogene activation and Tumor suppressor inactivation lead to Disrupted Genome integrity

A

True

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13
Q

Disrupted Genome integrity leads to more Oncogene activation and Tumor suppressor inactivation

A

true

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14
Q

what is aneuploidy and how is it caused

A

Generation of abnormal chromosome numbers in mitosis

through mis-segregation of chromosomes

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15
Q

what are lagging chromosomes

A

chromosomes that do not segregate properly

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16
Q

what can result from lagging chromosomes

A

aneuploidy

or

Chromothripsis

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17
Q

what is Chromothripsis

A

chromosome is in a micronucleus

not as protected, therefore get shattered

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18
Q

what causes aneuploidy

A

Inappropriate kinetochore-MT attachments
- caused by Compromised Spindle Assembly Checkpoint (rare in cancer)

Supernumerary centrosomes - centrosome overduplication (cancer and microcephaly

Problems in chromosome cohesion
- Tetraploidy (4n) – cytokinesis failure, cell fusion, endoreduplication (G1-S-G2-G1-S-G1

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19
Q

give exceptions of when aneuploidy is not lethal

A

Down’s syndrome (Chr21 Trisomy)

Rare patients with mosaic trisomy (12,18,21)

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20
Q

how does aneuploidy leads to substantial cellular fitness loss

Study These Flashcards
A

causes:

Impaired proliferation

Metabolic alterations

Defective stress responses

21
Q

what cells can survive aneuploidy

Study These Flashcards
A

Hepatocytes,

neural progenitors,

neurons

Highly present in CANCER

22
Q

How do cancer cells tolerate aneuploidy?

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A

lowering DNA damage response (i.e p53 mutations)

Increasing replication stress tolerance

prolonged mitosis (SAC)

23
Q

Certain level of CIN can be beneficial to cancer but too much is harmful

24
Q

How do cancer cells benefit from aneuploidy?

Study These Flashcards
A

Certain aneuploidies might favor tumorigenesis

Provides genetic diversity, substrate for tumor evolution:
- Certain aneuploidies correlate with metastasis, promoting EMT

25
what aneuploidies would favor tumorigenesis
- Trisomy Chr12 is associated with increase proliferation and tumorigenicity of hESC - In a colorectal cancer cell line single trisomies confer a selective advantage and increased tumorigenic behavior upon stress (starvation, hypoxia)
26
What happens when a cell is forced into the cell cycle?
ABL protoncogene activation it operates in the G1-S transition in response to mitogens ABL is a tyrosine kinase that becomes aberrantly activated as a result of a reciprocal translocation leads to the formation of BCR-ABL chimeric protein which is the cause of Chronic Myeloid Leukemia (CML)
27
what do Chromosome translocations arise from
aberrant repair of double stranded break DSB in interphase
28
what agents promote DSB
DNA topoisomerase II poisons Radiation chromosome instability CIN
29
what miss-guides DSB repair
Sequence homology at chromosome breakpoint The 3D chromosomal organization in interphase
30
give an examples of genes that can get translocated
ABL 1b and BCR
31
what does BCR- ABL oncogene do to the ABL kinase
prevents ABL inhibition (Releases SH3 SH2 internal inhibition) activates ABL kinase and it becomes cytoplasmic Promotes oligomerization and autophosphorylation
32
what does BCR-ABL oncogene result in in the cell
RAS-MAPK activation AKT activation JAK-STAT activation RAC GTPase signaling (cell proliferation) Production of MYC protooncogene and the anti-apoptotic proteins BCL-2, and BCL-X all the above results in Promotion of cell proliferation and survival
33
what disease is caused by BCR-ABL oncogene
chronic myeloid leukemia
34
give a way in which chronic myeloid leukemia is effectively treated
inhibition of ABL1 by imatinib
35
what do Chromosome rearrangements lead to
Gene fusions leading to a hybrid/chimeric gene frequently targeting transcription factors and tyrosine kinase ( i.e. BCR- ABL). Observed in hematological disorders and solid tumors. Alterations in gene expression - Over-expression of the MYC gene under immunoglobulin gene enhancers that re-localise to the proximity of the MYC gene upon translocation. Observed in lymphoid leukemias and in lymphomas of B and T cell - Promoter swapping also observed in solid tumors
36
which gene makes a cell exit the cell cycle
Rb (retinoblastoma protein)
37
what are the features of Rb
Operates in the G1-S transition – cell cycle start Most recently other cell cycle roles for Rb have been identified Deletions and frameshifts (premature stop) that lead to loss of Rb function are observed in children retinal tumors. Rb inactivation predisposes patients to many types of cancer. Patients typically exhibit defects in other pathways affecting cell growth and division (i.e p53).
38
describe the Rb canonical mechanism of action
Rb sequesters E2F, keeping G1-S cyclin gene off before G1 starts growth signals and cytokines lead to hyperphosphorylation of Rb this releases E2F transcription factor activating G1-S cyclin gene
39
G1-S cyclin gene and E2F are protooncogenes
true
40
what disease is linked with Rb
Retinoblastoma, a rare childhood eye tumor that arises in the precursors to photoreceptor cells
41
what are the 2 types of Retinoblastoma
Sporadic Familial
42
what are the features of Familial Retinoblastoma
inheritance form of the disease bilateral (both eyes), high risk of other cancers
43
what are the features of Sporadic Retinoblastoma
family has no history unilateral (one eye), no increase risk of cancer in other organs
44
once one copy of the Rb gene is mutated, the person is one step away from losing RB or other tumor suppressor in a particular organ what does that lead to
hetrozygus people can inherit the condition
45
why is it hard to design a targeted therapy for Rb cancers
the role of Rb is pleiotropic in the cell cycle it is difficult to know how Rb alterations (i.e.mutations) are affecting Rb function it is hard to design a targeted therapy (unlike BCR-ABL cancers) In addition we need to consider the genomic heterogeneity intrinsic to cancers, which could favor treatment resistance
46
Cancer cells rely more in replicative stress and SAC checkpoints than normal cells
true
47
what do conventional approaches to cancer aim to achieve
Promoting extreme chromosomal alterations by: forcing cell cycle exit induce replication stress induce DNA damage induce mitotic defects
48
what do novel approaches to cancer aim to achieve
induce cell progression (proliferation) impair replication stress tolerance by using ATRi or CHK1i to inhibit RSC response (RSC inhibits DNA replication stress) impair SAC by MPS1i (SAC inhibits mitotic defects)
49
Check slide 24
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BMS2002 (21 decks)

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