L22 Flashcards
give examples of cells that never divide
Mature muscle (cardiac muscle cells)
nerve cells
what cells are Arrested in G0 but can resume proliferation
Skin Fibroblast, smooth muscle cells, endothelial cells from blood vessels, epithelial cells (liver, pancreas, kidney, lung, prostate, breast)
what cells need a continuous cell renewal
Blood cells, intestinal epithelial cells
what does DNA damage checkpoint inhibit
CDK4/6, CDK2, and CDK1/2
what does the replication stress checkpoint inhibit
CDK1/2
what does the spindle assembly checkpoint inhibit
APC/C
what cells are mutated in cancer
Protooncogenes
Tumor suppressors
what are Protooncogenes
genes that promote cell growth and proliferation
what are oncogenes
mutated protooncogene in cancer
give an example of a protooncogene
ABL
give an example of tumor suppressor
Rb
Oncogene activation and Tumor suppressor inactivation lead to Disrupted Genome integrity
True
Disrupted Genome integrity leads to more Oncogene activation and Tumor suppressor inactivation
true
what is aneuploidy and how is it caused
Generation of abnormal chromosome numbers in mitosis
through mis-segregation of chromosomes
what are lagging chromosomes
chromosomes that do not segregate properly
what can result from lagging chromosomes
aneuploidy
or
Chromothripsis
what is Chromothripsis
chromosome is in a micronucleus
not as protected, therefore get shattered
what causes aneuploidy
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
give exceptions of when aneuploidy is not lethal
Down’s syndrome (Chr21 Trisomy)
Rare patients with mosaic trisomy (12,18,21)
how does aneuploidy leads to substantial cellular fitness loss
causes:
Impaired proliferation
Metabolic alterations
Defective stress responses
what cells can survive aneuploidy
Hepatocytes,
neural progenitors,
neurons
Highly present in CANCER
How do cancer cells tolerate aneuploidy?
lowering DNA damage response (i.e p53 mutations)
Increasing replication stress tolerance
prolonged mitosis (SAC)
Certain level of CIN can be beneficial to cancer but too much is harmful
True
How do cancer cells benefit from aneuploidy?
Certain aneuploidies might favor tumorigenesis
Provides genetic diversity, substrate for tumor evolution:
- Certain aneuploidies correlate with metastasis, promoting EMT
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)
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)
what do Chromosome translocations arise from
aberrant repair of double stranded break DSB in interphase
what agents promote DSB
DNA topoisomerase II poisons
Radiation
chromosome instability CIN
what miss-guides DSB repair
Sequence homology at chromosome breakpoint
The 3D chromosomal organization in interphase
give an examples of genes that can get translocated
ABL 1b and BCR
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
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
what disease is caused by BCR-ABL oncogene
chronic myeloid leukemia
give a way in which chronic myeloid leukemia is effectively treated
inhibition of ABL1 by imatinib
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
which gene makes a cell exit the cell cycle
Rb (retinoblastoma protein)
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).
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
G1-S cyclin gene and E2F are protooncogenes
true
what disease is linked with Rb
Retinoblastoma, a rare childhood eye tumor that arises in the precursors to photoreceptor cells
what are the 2 types of Retinoblastoma
Sporadic
Familial
what are the features of Familial Retinoblastoma
inheritance form of the disease
bilateral (both eyes),
high risk of other cancers
what are the features of Sporadic Retinoblastoma
family has no history
unilateral (one eye),
no increase risk of cancer in other organs
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
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
Cancer cells rely more in replicative stress and SAC checkpoints than normal cells
true
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
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)
Check slide 24
GOOD LUCK
