Path: Cell Cycle and Cancer Basics Flashcards
What are the key elements of cellular proliferation?
- accurate DNA replication
- coordinated synthesis of all other cell constituents
The term “cell cycle” refers to what?
the sequence of events that results in cell division
The cell cycle consists of what 4 phases?
- G1 phase - pre-synthetic growth
- S - DNA synthesis phase
- G2 - pre-mitotic phase
- M - mitotic phase
The G0 phase of the cell cycle contains what kind of cells?
quiescent cells not actively cycline
When can cells enter the G1 phase?
either from G0 quiescent pool, or after completing a round of mitosis (as for continuously replicating cells)
True or false: each phase of the cell cycle requires completion of the previous phase, as well as activation of necessary cofactors.
True
Nonfidelity of DNA replication or cofactor deficiency results in what?
cell cycle arrest at transition points
What are labile tissue cells?
cells that cycle continuously; include those of the GI tract and epidermis
What are stable cells?
those that are normally quiescent but can enter the cell cycle if needed; include hepatocytes
What are permanent cells?
those that have lost the capacity to proliferate; include cardiac myocytes and neurons
What does the heart do to compensate when cardiac myocytes have been lost?
hypertrophy of the remaining myocytes, up to a point
Check for damaged or unduplicated DNA occurs at the __/__ checkpoint.
G2/M
True or False: The cell cycle is activated by regulators and inactivators.
False - the cell cycle is regulated by activators and inhibitors.
What are cyclins?
proteins that drive cell cycle progression; they are named for the cyclic nature of their production and degradation
What are CDKs?
cyclin-dependent kinases; they are enzymes that associate and form complexes with cyclins to phosphorylate protein substrates
Transiently increased synthesis of a particular cyclin leads to increased ____ activity of the associated ____.
kinase; CDK binding partner
True or false: after the CDK completes its round of phosphorylation, the associated CDK is degraded.
False - the associated cyclin is degraded, and CDK activity ceases
True or false: as the levels of cyclin rise and fall, so does the activity of associated CDKs.
True
Which Cyclin-CDKs regulate the transition of G1 to S phases?
Cyclin E-CDK2
Cyclin D-CDK4
Cyclin D-CDK6
*2-4-6
Which cyclins are active in the S phase?
Cyclin A-CDK1
Cyclin A-CDK2
Cyclin __-CDK__ is essential for the G2 to M transition.
Cyclin B-CDK1
The G1-S checkpoint ensures what, whereas the G2-M restriction point ensure what?
G1-S = DNA integrity, before irreversibly committing cellular resources to DNA replication G2-M = accurate genetic replicatoin before the cell actually divides
If/when cells detect DNA irregularities, ____ ____ delays cell cycle progression and triggers ____ ____.
checkpoint activation; DNA repair
When will cell cycle checkpoints signal the cell to undergo apoptosis?
when there is genetic derangement that is too severe to be repaired
What is the job of CDKIs? (CDK inhibitors)
to enforce the cell cycle checkpoints by modulating CDK-cyclin complex activity
One family of CDKIs broadly inhibits multiple CDKs. What 3 proteins are in this family?
p21, p27, p57
One family of CDKIs selectively inhibits some CDKs. What 4 proteins are in this family, and which CDKs do they inhibit?
p15, p16, p18, p19
CDK4 and CDK6
What stimulates the production of other cellular components that are needed to make two daughter cells?
growth factors - this signaling promotes cell cycle progression as well as growth and changes in cell metabolism that promote growth
What is the Warburg effect?
increased cell uptake of glucose and glutamine, increased glycolysis and decreased oxidative phsphorylation; present in growing and dividing cells
What features of the Warburg effect enable PET scans to identify malignant tumors?
the fact that cancer cells have increased glucose uptake; so in a PET scan when fluorodeoxyglucose (a non-metabolizeable glucose derivative) is administered, much more of it is taken up by cancer cells, and seen more concentrated in malignancies over normal tissues
In receptor mediated signaling: intracellular receptors are ____ ____ that are activated by ____-soluble ligands that can easily cross the plasma membrane.
transcription factors; lipid
Vitamin D and steroid hormones are hydrophobic ligands that activate what kind of intracellular receptors?
nuclear hormone receptors
these are what normally bind estrogens and androgens for growth, important in cancers
What are 4 activities that can result from EC binding of a receptor ligand?
- opening of ion channels
- activate associated GTP-binding regulatory protein (G protein)
- activate endogenous or associated enzyme (often tyrosine kinase)
- trigger proteolytic event or a change in protein binding or stability that activates a latent transcription factor
Describe the non-receptor tyrosine kinase signaling pathway.
TM receptor binds EC ligand and IC an associated kinase phosphoylates the receptor for subsequent function
Describe the receptor tyrosine kinase signaling pathway.
TM receptor binds EC ligand which causes receptor dimerization, auto-phosphorylation of tyrosine residues by kinase domain; adaptor proteins present couple the receptors to inactive GDP-bound Ras; GDP is replaced by GTP and kicks off phosphorylation cascades:
(1) Ras–>Raf/MAPKK–>MEK–>ERK–>TFs (MAPKK all the way down to MAP)
(2) PI3K–>Akt–>mTOR–>TFs
Describe the GPCR signaling pathway.
ligand binds EC; the 7 TM domain receptor bound to heterotrimeric G proteins ultimately influences conversion of ATP–>cAMP
Describe the nuclear receptor signaling pathway.
an IC receptor binds nuclear hormone that comes into the cell; together the receptor-ligand complex translocates to the nucleus and influences transcripton
Describe the Notch signaling pathway.
Notch ligand binds EC; cleavage of Notch (TM protein) releases an IC notch fragment that can enter the nucleus and influence transcription of specific target genes
Describe the Wnt/frizzled signaling pathway.
activation releases intracellular beta-catenin from a protein complex thtat normally drives its constitutive degradation, so beta-catenin is freed to migrate to the nucleus and act as a TF
Normally activated Ras hydrolyzes GTP to GDP which inactivates Ras and there’s no more Ras activation of Raf. Mutations in Ras that delay this hydrolysis step can lead to what?
augmented proliferative signaling, and cancer
Alterations in tyrosine kinase receptor geometry can have what effect?
elicit intrinsic receptor protein kinase activity, or promote the enzymatic activity of recruited IC kinases, which results in downstream phosphorylation
True or False: tyrosine kinase inhibitors are important in cancer treatment.
True
What do each of these drugs do, and what cancers are they typically used for?:
Imatinib
Erlotinib
Sunitinib
Imatinib–inhibits tyrosine kinase in chronic myelogenous leukemia
Erlotinib–inhibits tyrosine kinase in some lung cancers
Sunitinib–inhibits tyrosine kinase in some kidney cancers
Tyrosine kinase inhibitors given to treat cancer are taken ____ and are generally much ____ toxic than cytotoxic chemotherapy.
orally; less
When GPCRs are bound by EC ligand, what happens with respect to GDP/GTP?
a protein that has GDP bound associates with the GPCR; this is the G protein. This GDP is replaced by GTP and the G protein is activated.
Wnt pathway involves the ____ family of TM receptors, which regulate IC levels of ____.
Frizzled; beta-catenin
Normally, beta-catenin is constantly targeted for ____-directed proteasome degradation..
ubiquitin
When Wnt binds to Frizzled, another IC protein called ____ is recruited that leads to disruption of the ________ complex.
Disheveled; beta-catenin degradation-targeting complex
Wnt/Frizzled/beta-catenin pathway is important in what type of cancer?
colon cancer
MYC and JUN are transcription factors that regulate the expression of genes for what?
cell growth
Where do most transcription factors bind?
in long-range regulatory elements such as enhancers; enhancers are usually located nearby to genes but are sometimes far away
For a transcription factor to induce transcription, it must also possess protein:protein interaction domains that do what?
directly or indirectly recruit:
histone modifying enzymes, chromatin remodeling complexes, and RNA polymerase
Growth factor activity is mediated through binding to specific receptors, ultimately influencing the expression of genes that can do what?
- promote entry of cells into cell cycle
- relieve blocks on cell cycle progression (promoting replication)
- prevent apoptosis
- enhance biosynthesis of cellular components required for daughter cells (like nucleic acids, proteins, lipids, carbs)
What are the two periods at which growth factors are involved in the proliferation of cells?
- at steady state (for labile cells)
- after injury
Many growth factor pathways genes are proto-oncogenes. This means what?
means that gain-of-function mutations in these genes can convert them into oncogenes capable of driving unfettered cell proliferation and tumor formation
Describe the epidermal growth factor receptor family (EGFR).
this family of proteins includes 4 membrane receptors with intrinsic tyrosine kinase activity; best characterized is EGFR1 (aka ERB-B1, or EGFR); mutations in EGFR1 frequently occur in a number of cancers (lung, head, neck, breast, brain)
The ____ receptor is overexpressed in a subset of breast (and other) cancers.
ERB-B2 (aka HER2)
What do the drugs Trastuzumab and Pertuzumab do?
they are both antibodies against the ERB-B2/HER2 receptors; Trastuzumab prevents ligand-independent signaling while Pertuzumab inhibits ligand-dependent signaling; both activate ADCC
True or false: cancers usually have a polyclonal origin.
False - cancers usually have a monoclonal origin; they arise from a single abnormal cell
What two heritable properties define cancer cells?
- they reporduce in defiance of the normal restraints on cell division
- thy invade and colonize territories normally reserved for other cells
Cancers develop in stages via ____ ____.
clonal evolution; such as: normal -->low-grade intraepithelial neoplasia -->high-grade intraepithelial neoplasia -->invasive carcinoma
General properties involved with converting cells to cancer cells include:
- loss of normal regulation of proliferation (GF independence, loss of density-dependent contact inhibition)
- avoid apoptosis
- genetic instability
- escape from proper site (invasiveness)
- survive and proliferate in distant sites (metastasis)
What are oncogenes?
genes that act in a dominant fashion to stimulate or sustain replication; the mutation here that causes cancer is a “gain of function” mutation
What are tumor suppressor genes?
genes that act in a recessive manner resulting in either increased or sustained proliferation or decreased DNA repair; mutation in these cgenes that causes cancer is a “loss of function” mutation, and it must be present in both copies of the gene to induce cancer
Proto-oncogenes can become oncogenic via what 4 ways?
- coding sequence mutation that makes normal amounts but of a hyperactive protein
- gene amplification to overproduce normal protein
- chromosome rearrangement to overproduce normal protein
- chromosome rearrangement resulting in hyperactive or overproduced fusion protein
What are the two classifications of tumor suppressor genes, and how do they regulate?
- gatekeepers - directly regulate cell growth
- caretakers - repair DNA damage, maintain genomic integrity
True or false: it takes mutations in both proto-oncogenes to cause cancer, but only one mutation in a tumor suppressor gene.
False: it takes mutations in both tumor suppressor genes to cause cancer, but only one mutation in a proto-oncogene.
The lymphatic pattern of metastatic spread is typical of ____.
carcinomas (cancer from epithelium or organ lining)
The hemtogenous (to lung/liver) pattern of metastatic spread is typical of ____.
sarcomas (tumor of connective tissue or non-epithelium)
The seeding (of body cavities/surfaces) pattern of metastatic spread is typical of ____.
ovarian carcinoma
Describe the essential differences between oncogenes and tumor suppressor genes.
Oncogenes- drive autonomous cell growth in cancer cells (accelerator pedal) One good proto-oncogene can be dominated by its companion proto-oncogene gone bad.
Tumor suppressor genes- control cell proliferation (defects are like faulty breaks) One good tumor suppressor gene is sufficient to prevent cancer, pathological defects require both copies to be mutated.
What type of molecular test/study would provide good evidence that proliferating cells are neoplastic?
a test showing that the cells all share some oncogene or tumor suppressor gene mutation(s)
Metastatic ovarian carcinoma characteristically causes ____ ____ which could present as nausea and vomiting.
intestinal obstruction
