H&N tumor biology and carcinogenesis Flashcards
What are the five basic phases of the cell cycle,
and what occurs during each phase?
● Quiescent phase (G0): Resting state
● Gap 1 (G1): Preparation for cell division; increase in transcription/translation and ~ doubling of macromolecules
● Synthesis phase (S): Replication of chromosomes
● Gap 2 (G2): Continued cellular growth
● Mitosis phase (M): Chromosomes are separated, and two
daughter cells result
What is the term given to cells in permanent cell-
cycle arrest?
Senescent
What are the key checkpoints within the cell cycle?
● G1/S checkpoint (“restriction point”): Prevent entry into
S-phase, rate-limiting step
● Intra-S phase checkpoint: Halt progression of S-phase if
damaged DNA is detected
● G2/M checkpoint: Prevent entry into M phase
● M checkpoint: Ensure correct replication of DNA and avoid
mitotic exit if errors exist
If a lesion (i.e., partially replicated DNA, strand
breaks, or other errors) is identified at a check-
point, what processes can be activated?
● Recruitment of DNA repair effector complexes
● Temporary cell-cycle arrest, which can lead to senescence
or apoptosis, depending on the cell and the lesion
What key tumor suppressor protein controls pro-
gression through the G1/S checkpoint (restriction point) and the G2/M checkpoint?
p53 (activates p21 → inhibits cyclin and cyclin-dependent
kinase (Cdk) complexes)
What two key classes of molecules regulate a cell’s
progress through the cell cycle?
● Cdks: Catalytic subunit; require cyclin for activation; result
in phosphorylation (activates/inactivates molecules nec-
essary for progression through the cell cycle)
● Cyclins: Regulatory subunit that activates Cdk molecules
when bound to form a heterodimer
Although more than 15 Cdks have been identified,
four have key biologic functions within the cell
cycle. What are they, and what do they do?
● Cdk 1: Controls G2 phase and M phase (prophase) →
Cyclin A dependent
● Cdk 2: Controls G1 to S transition and S phase → cyclin E
(and A) dependent
● Cdk 4: G0 to G1 transition → cyclin D dependent
● Cdk 6: G0 to G1 transition → cyclin D dependent
Specific families of activators and inhibitors regulate functional activities of the Cdk com-
plexes. Identify the primary activators and inhibitors.
● Activators: Cdk-activating kinase (CAK) and Cdc-25
● Inhibitors: Cdk inhibitors (CKI) → Inhibitor of kinase 4
(INK4a), Cdk Interacting protein/kinase inhibitory protein
(Cip/Kip)
What type of gene helps to control cell growth or
progression through the cell cycle?
Tumor suppressor gene (also called antioncogenes)
What type of gene promotes cell growth and
progression through the cell cycle?
Proto-oncogenes. Once a proto-oncogene is mutated, it is
known as an oncogene.
The classic retinoblastoma tumor suppressor protein (pRb) functions to inhibit what key transcription factors, effectively preventing formation of cell cycle–related proteins and arresting the cell
in G0 phase?
E2F factors
Phosphorylation of pRb by what important cyclin- Cdk complex(es) results in dissociation of pRb from E2F and subsequent entrance into the cell cycle?
Cyclin D-Cdk4 and cyclin D-Cdk6
Release of E2F from pRb inhibition results in the
transcription of multiple genes necessary for the
function of the cell cycle. Transcription of what key cyclin protein results in activation of Cdk2, progression from G1 to S phase, additional pRb inactivation, and p27 degradation?
Cyclin E
What genes are considered members of the Cip/
Kip family of tumor suppressor genes, and in what
phase of the cell cycle do they inhibit cyclin-Cdk
complexes?
● p21, p27, and p57
● G1 phase
DNA damage results in activation of what key tumor-
suppressor gene and proapoptotic factor, which in turn activates p21 (a Cip/Kip Cdk complex inhibitor)
and results in arrest of the cell cycle in G1 phase?
p53
Transforming growth factor-β is a growth inhibitor,
which results in activation of which INK4 tumor
suppressor gene causing subsequent cell-cycle
arrest in G1 phase?
p27
What genes are considered members of the INK4a
family of tumor-suppressor genes, and in what
phase of the cell cycle do they inhibit cyclin-Cdk
complexes?
● p16 and p19
● G1 phase
Name the tumor suppressor gene that is a
member of the INK4a family that prevents p53
degradation and therefore results in cell-cycle
arrest at the G1-checkpoint.
p19
Name the tumor suppressor gene that is a member of the INK4a family that inhibits cyclin D-Cdk4/6 complexes and therefore results cell cycle arrest during the G1 phase.
p16
What important enzymes function to dephos-
phorylate the targets of cyclin-Cdk complexes, such as pRb?
PP1 and PP2A (phosphatases)
To promote an orderly progression through the
cell cycle, cyclin-Cdk complexes must be degraded
to allow the next phase of the cell cycle to
progress uninterrupted. For example, S-phase
complexes cannot be active during M phase and so forth. What important enzymatic process selectively targets these complexes for degradation?
Ubiquitin-dependent protein degradation (ubiquitylation)
The phases G1, S, and G2 are collectively referred
to as what?
Interphase
What are the five stages of mitosis (M phase)?
● Prophase: Preparatory; cyclin A-Cdk1 active; condensation
of chromatin, polarization of centrosomes, and initiation
of mitotic spindle formation
● Prometaphase: Nuclear envelope breaks down, mitotic
spindle microtubules attach to chromosomes
● Metaphase: Alignment of chromosomes at metaphase
plate
● Anaphase: Separation of sister chromatids
● Telophase: Cytoplasmic division (cytokinesis) into two
daughter cells; chromatid decondensation (expansion)
Describe the “two-hit” hypothesis (Knudson,
1971) for carcinogenesis.
Loss of two alleles for a tumor-suppressor gene is necessary
to result in loss of function and tumorigenesis. This
hypothesis is not applicable to proto-oncogenes and
dominant negative tumor suppressor genes (e.g., p53).
