4 cell cycle Flashcards
What is cell growth?
Cell growth refers to alterations in the size of a cell mass, controlled by proliferation, differentiation, and apoptosis.
What is cell proliferation?
It is the process by which cells divide to produce daughter cells, increasing the total number of cells.
What is cell differentiation?
It is the process by which progenitor cells gain specialized functions to perform distinct biological roles.
What is apoptosis?
Apoptosis is programmed cell death that removes cells that are not fit to function within a specific niche.
How do cancers exhibit elevated cell growth?
Cancer cells have increased proliferation, reduced differentiation, and/or diminished apoptosis, leading to abnormal cell mass formation.
What happens to the number of proliferating cells in healthy tissue?
The number of proliferating cells remains constant due to a balance between cell division and cell death.
What happens if apoptosis and differentiation are blocked while proliferation remains unchanged?
There is an increase in the abundance of proliferating cells, leading to abnormal growth.
What happens if proliferation increases without changes in apoptosis or differentiation?
The number of proliferating cells increases, disrupting normal tissue homeostasis.
How does the colonic villus model illustrate controlled cell fates?
Stem cells in the crypts give rise to progenitor cells, which proliferate and then differentiate as they migrate, forming the colonic epithelium.
Why is the colonic epithelium highly dependent on cell proliferation and differentiation?
The colon has a high turnover rate, requiring constant renewal of epithelial cells to maintain function.
What happens when there is an imbalance in proliferation and differentiation?
It can lead to cancer due to excessive proliferation and loss of proper cell function.
What are the key factors controlling cell fate?
Growth-promoting signals, growth-inhibiting signals, pro-apoptotic signals, and survival signals.
What determines whether a cell replicates or undergoes apoptosis?
The integration of positive (growth) and negative (inhibitory/apoptotic) signals.
How does cell fate regulation become disrupted in cancer?
Cancer cells lose proper control of signals, leading to unchecked proliferation and survival.
What phase are quiescent cells typically in?
The Gap 0 (G0) phase.
What signals push cells to enter the cell cycle from G0?
Growth-promoting signals.
What is the role of survival signals in the cell cycle?
They allow cells to transition through key checkpoints and avoid apoptosis.
What is the role of the G1 phase in the cell cycle?
It prepares the cell for division by increasing organelles and macromolecules.
What happens during the S phase?
DNA replication occurs, ensuring genetic material is copied before division.
What is the function of the G2 phase?
It allows DNA integrity to be assessed and prepares the cell for mitosis.
What occurs during mitosis (M phase)?
Chromosomes condense, align, separate, and the cytoplasm divides, producing two daughter cells.
What are cyclin-dependent kinases (CDKs)?
A family of serine/threonine kinases that regulate cell cycle progression by phosphorylating key substrates.
How do CDKs become active?
They form holoenzyme complexes with their respective cyclins, which are required for activation.
What is the function of CDK inhibitors (CKIs)?
They regulate CDK activity by preventing excessive cell cycle progression.
What is the function of CDK2-Cyclin A?
It regulates substrates involved in DNA replication and repair.
What is the role of CDK1-Cyclin A/B?
It regulates chromosomal alignment and separation during mitosis.
Why is CDK1 essential for the cell cycle in mammals?
It is the only CDK required for cell division.
What are the two types of CDKs in the human genome?
Cell cycle-related and transcriptional CDKs.
How is CDK activity regulated?
By phosphorylation-dependent mechanisms and CDK inhibitors.
What is p53’s role in cell cycle regulation?
It acts as a checkpoint regulator that controls the G1/S and G2/M transitions.
What activates p53 in response to DNA damage?
The kinases ATM and ATR, which phosphorylate p53 to increase its levels.
What are the three possible outcomes of p53 activation?
Cell cycle arrest, DNA repair, or apoptosis.
How is p53 kept in check under normal conditions?
The E3 ubiquitin ligase MDM2 degrades p53 to prevent unnecessary interference with the cell cycle.
What happens when p53 is mutated in cancer?
Cells fail to pause the cell cycle, repair DNA damage, or undergo apoptosis, allowing cancerous mutations to persist.
Why is CDK4/6 inhibition a viable cancer therapy?
Blocking CDK4/6 prevents pRb phosphorylation, halting cell cycle progression at G1.
What is Ribociclib?
An ATP-competitive inhibitor of CDK4/6 that prevents its kinase activity.
How does CDK4/6 inhibition affect cancer cells?
It stops uncontrolled cell division, reducing tumour growth.
Why is reactivating wild-type p53 a potential therapy?
Many cancers have normal p53, but its function is inhibited by overactive MDM2.
What is Nutlin-3a/RG7112?
A small molecule that prevents MDM2 from degrading p53, restoring its tumour-suppressing function.
What is the consequence of pRb loss in cancer?
Cells can enter S phase without mitogenic stimulation, increasing cancer risk.
What genes does p53 regulate for DNA repair?
POLK, KU86, and XPC.
What is the role of the G1/S checkpoint?
It ensures that DNA is undamaged before replication begins.
What is the G2/M checkpoint?
It prevents mitosis if there are errors in DNA replication.
How do CDK inhibitors like p16 function?
They block CDK4/6 from binding to Cyclin D, preventing cell cycle progression.
Why are CDK inhibitors commonly lost in cancer?
Their loss allows unchecked cell cycle progression, increasing tumour growth.
What happens when pRb is phosphorylated?
It releases E2F, allowing transcription of genes required for S phase entry.
What is the function of E2F?
It promotes the expression of genes involved in DNA replication and S phase progression.
Why is targeting MDM2 a promising cancer therapy?
Inhibiting MDM2 allows p53 to function properly and induce cell cycle arrest or apoptosis.
Why haven’t MDM2 inhibitors been approved for clinical use yet?
Although promising, they require further validation in clinical trials.
How do cancer therapies target deregulated cell cycle mechanisms?
By inhibiting CDKs, reactivating p53, or blocking key pathways that drive uncontrolled proliferation.
What are mitogens, and how do they influence the cell cycle?
Mitogens are extracellular signals (e.g., EGF, PDGF) that stimulate cells to enter the cell cycle by activating receptor tyrosine kinases and downstream signalling pathways like Ras/MAPK, leading to Cyclin D upregulation.
How does the Myc proto-oncogene regulate cell cycle progression?
Myc promotes cell cycle entry by increasing Cyclin D expression, repressing CDK inhibitors (e.g., p21 and p27), and enhancing ribosomal biogenesis for cell growth.
What is cellular senescence, and how does it relate to cancer prevention?
Senescence is a state of irreversible cell cycle arrest in response to stress (e.g., telomere shortening, oncogene activation). It prevents uncontrolled proliferation and acts as a tumour suppressor mechanism.
How does p53 regulate the G1/S checkpoint?
When DNA damage is detected, p53 activates p21, which inhibits CDK2-Cyclin E, preventing Rb phosphorylation and halting cell cycle progression at G1/S
What are the pro-apoptotic targets of p53, and how do they induce cell death?
p53 upregulates pro-apoptotic genes like BAX, PUMA, and NOXA, which inhibit anti-apoptotic proteins (e.g., BCL-2, MCL-1), leading to mitochondrial permeabilization and apoptosis.
How does the ATM/ATR pathway influence p53 activation?
: Upon DNA damage, ATM and ATR kinases phosphorylate p53, stabilizing it by preventing MDM2-mediated degradation, allowing p53 to induce DNA repair or apoptosis.
How do cancer cells develop resistance to CDK4/6 inhibitors?
Resistance mechanisms include loss of pRb (making CDK4/6 inhibition ineffective), Cyclin E overexpression (bypassing CDK4/6 control), and activation of alternative pathways like PI3K/AKT.
Why are CDK4/6 inhibitors often combined with hormonal therapies in ER+ breast cancer?
ER+ breast cancer relies on oestrogen signalling for growth. Combining CDK4/6 inhibitors with hormonal therapy (e.g., aromatase inhibitors) enhances anti-proliferative effects by blocking both oestrogen-driven and CDK4/6-mediated cell cycle progression.
What other cell cycle regulators are being explored for cancer therapy?
Other targets include WEE1 kinase inhibitors (which prevent CDK1 activation and force mitotic catastrophe) and Aurora kinase inhibitors (which disrupt mitotic spindle assembly).
