Cell cycle and disease Flashcards
lecture 22
Which cells never divide after development?
Mature muscle cells (e.g., cardiac muscle) and nerve cells.
Name examples of cells arrested in G0 but capable of resuming proliferation.
Skin fibroblasts, smooth muscle cells, endothelial cells (blood vessels), epithelial cells (liver, pancreas, kidney, lung, prostate, breast).
Which tissues rely on continuous renewal by stem cells?
Blood cells and intestinal epithelial cells.
How many cells are in an adult human, and how many divide daily?
40 trillion cells, with millions dividing daily for growth and repair.
What ensures cell cycle exit upon DNA damage or errors?
Surveillance mechanisms.
What happens when cell cycle controls fail, and cells cannot exit the cycle?
Cancer develops, with uncontrolled division leading to mutations and genomic instability.
What are proto-oncogenes, and what happens when they mutate?
Genes that regulate cell division. When mutated (oncogenes), they mimic a “stuck accelerator,” causing uncontrolled growth and division.
What is the role of tumor suppressors like p53?
Ensure cell cycle exit upon DNA damage. Loss of function leads to defective cycle control and cancer.
What percentage of solid tumors show aneuploidy?
~70%.
How do cancer cells tolerate aneuploidy?
By mutating p53, increasing replication stress tolerance, and relying on spindle assembly checkpoints (SAC).
What is the significance of chromosome translocations in cancer?
They can activate oncogenes (e.g., ABL) or disrupt tumor suppressors, driving cancer progression.
What is the cause of Chronic Myeloid Leukemia (CML)?
The BCR-ABL oncogene resulting from chromosome 9 and 22 translocation.
What does Rb (retinoblastoma protein) do in the cell cycle?
Prevents entry into the cell cycle by regulating the G1-S transition via the E2F pathway.
How does Rb inactivation contribute to cancer?
Leads to loss of cell cycle control, genomic instability, and predisposes patients to various cancers.
How do cancer cells benefit from chromosomal instability (CIN)?
CIN provides genetic diversity, aiding tumor evolution and metastasis.
What is a key therapeutic strategy targeting cancer cell cycle abnormalities?
Exploiting their reliance on replication stress and SAC checkpoints to induce catastrophic DNA damage.
What are the consequences of cell cycle failure during chromosome segregation?
Propagation of mutations, genomic instability, and aneuploidy.
What is chromothripsis, and how is it related to cancer?
Chromothripsis is extreme chromosome rearrangement that occurs due to erroneous double-strand break (DSB) repair, often contributing to cancer progression.
What causes aneuploidy during mitosis?
Aberrant kinetochore-microtubule attachments.
Supernumerary centrosomes.
Problems in chromosome cohesion.
Cytokinesis failure or cell fusion.
What role does p53 play in maintaining genomic integrity?
p53 activates a DNA damage response, halting the cell cycle to repair errors or induce apoptosis if errors persist.
What is the relationship between trisomy and cancer?
Certain trisomies (e.g., Chr12 in colorectal cancer) can enhance tumorigenicity and provide selective advantages under stress conditions.
What is the spindle assembly checkpoint (SAC), and why is it important in cancer cells?
SAC ensures proper chromosome segregation during mitosis. Cancer cells rely heavily on SAC to avoid catastrophic chromosome missegregation despite chromosomal instability.
What is the role of the BCR-ABL chimeric protein in leukemia?
It promotes unchecked cell proliferation through RAS-MAPK, AKT, and JAK-STAT signaling pathways, leading to Chronic Myeloid Leukemia (CML).
How does imatinib target Chronic Myeloid Leukemia?
By inhibiting the ABL1 tyrosine kinase activity of the BCR-ABL fusion protein.
What is the significance of MYC proto-oncogene translocation in cancer?
MYC translocations place the gene under control of strong promoters, leading to overexpression and cancer, particularly in lymphomas.
What are the two types of retinoblastoma, and how do they differ?
Sporadic: Unilateral, no increased risk for other cancers.
Familial: Bilateral, high risk for other cancers due to inherited mutations in RB.
What is the impact of loss of Rb function on genomic stability?
Leads to chromosomal instability (CIN), defective DNA damage checkpoints, and improper mitotic progression.
What are the challenges in targeting Rb-related cancers therapeutically?
The pleiotropic role of Rb in cell cycle regulation makes it difficult to design specific treatments, compounded by genomic heterogeneity in cancers.
How do cancer cells exploit replication stress?
They enhance replication stress tolerance and rely on extended mitosis to prevent catastrophic damage from incomplete DNA replication or spindle assembly.
What is the role of supernumerary centrosomes in cancer?
They lead to improper chromosome segregation, contributing to aneuploidy and genomic instability.
What happens during a chromosome translocation?
Parts of chromosomes are exchanged incorrectly, often resulting in gene fusions (e.g., BCR-ABL) or misregulation of gene expression.
What is the connection between double-strand breaks (DSBs) and chromosome translocations?
Improper repair of DSBs can lead to chromosomal translocations and activation of oncogenes.
How does the Rb protein regulate the G1-S transition?
By binding and inhibiting E2F transcription factors, preventing expression of genes required for cell cycle progression.
Why is genome integrity critical in preventing cancer?
Disrupted genome integrity (via mutations, aneuploidy, or chromosomal alterations) leads to unchecked cell division and cancer development.
How does cancer use chromosomal instability (CIN) as an advantage?
CIN increases genetic diversity, aiding tumor evolution and allowing adaptation to therapeutic stress.
What are some promising strategies to target cancer’s reliance on CIN?
Promoting extreme chromosomal instability to induce cell death or targeting SAC reliance and replication stress pathways.
