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cmod/pcm- block 2 > Path: Cell Cycle and Cancer Basics > Flashcards

Path: Cell Cycle and Cancer Basics Flashcards

1
Q

What are the key elements of cellular proliferation?

A
  • accurate DNA replication

- coordinated synthesis of all other cell constituents

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2
Q

The term “cell cycle” refers to what?

A

the sequence of events that results in cell division

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3
Q

The cell cycle consists of what 4 phases?

A
  1. G1 phase - pre-synthetic growth
  2. S - DNA synthesis phase
  3. G2 - pre-mitotic phase
  4. M - mitotic phase
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4
Q

The G0 phase of the cell cycle contains what kind of cells?

A

quiescent cells not actively cycline

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5
Q

When can cells enter the G1 phase?

A

either from G0 quiescent pool, or after completing a round of mitosis (as for continuously replicating cells)

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6
Q

True or false: each phase of the cell cycle requires completion of the previous phase, as well as activation of necessary cofactors.

A

True

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7
Q

Nonfidelity of DNA replication or cofactor deficiency results in what?

A

cell cycle arrest at transition points

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8
Q

What are labile tissue cells?

A

cells that cycle continuously; include those of the GI tract and epidermis

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9
Q

What are stable cells?

A

those that are normally quiescent but can enter the cell cycle if needed; include hepatocytes

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10
Q

What are permanent cells?

A

those that have lost the capacity to proliferate; include cardiac myocytes and neurons

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11
Q

What does the heart do to compensate when cardiac myocytes have been lost?

A

hypertrophy of the remaining myocytes, up to a point

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12
Q

Check for damaged or unduplicated DNA occurs at the __/__ checkpoint.

A

G2/M

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13
Q

True or False: The cell cycle is activated by regulators and inactivators.

A

False - the cell cycle is regulated by activators and inhibitors.

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14
Q

What are cyclins?

A

proteins that drive cell cycle progression; they are named for the cyclic nature of their production and degradation

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15
Q

What are CDKs?

A

cyclin-dependent kinases; they are enzymes that associate and form complexes with cyclins to phosphorylate protein substrates

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16
Q

Transiently increased synthesis of a particular cyclin leads to increased ____ activity of the associated ____.

A

kinase; CDK binding partner

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17
Q

True or false: after the CDK completes its round of phosphorylation, the associated CDK is degraded.

A

False - the associated cyclin is degraded, and CDK activity ceases

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18
Q

True or false: as the levels of cyclin rise and fall, so does the activity of associated CDKs.

A

True

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19
Q

Which Cyclin-CDKs regulate the transition of G1 to S phases?

A

Cyclin E-CDK2
Cyclin D-CDK4
Cyclin D-CDK6
*2-4-6

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20
Q

Which cyclins are active in the S phase?

A

Cyclin A-CDK1

Cyclin A-CDK2

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21
Q

Cyclin __-CDK__ is essential for the G2 to M transition.

A

Cyclin B-CDK1

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22
Q

The G1-S checkpoint ensures what, whereas the G2-M restriction point ensure what?

A 
G1-S = DNA integrity, before irreversibly committing cellular resources to DNA replication
G2-M = accurate genetic replicatoin before the cell actually divides
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23
Q

If/when cells detect DNA irregularities, ____ ____ delays cell cycle progression and triggers ____ ____.

A

checkpoint activation; DNA repair

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24
Q

When will cell cycle checkpoints signal the cell to undergo apoptosis?

A

when there is genetic derangement that is too severe to be repaired

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25
Q

What is the job of CDKIs? (CDK inhibitors)

A

to enforce the cell cycle checkpoints by modulating CDK-cyclin complex activity

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26
Q

One family of CDKIs broadly inhibits multiple CDKs. What 3 proteins are in this family?

A

p21, p27, p57

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27
Q

One family of CDKIs selectively inhibits some CDKs. What 4 proteins are in this family, and which CDKs do they inhibit?

A

p15, p16, p18, p19

CDK4 and CDK6

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28
Q

What stimulates the production of other cellular components that are needed to make two daughter cells?

A

growth factors - this signaling promotes cell cycle progression as well as growth and changes in cell metabolism that promote growth

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29
Q

What is the Warburg effect?

A

increased cell uptake of glucose and glutamine, increased glycolysis and decreased oxidative phsphorylation; present in growing and dividing cells

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30
Q

What features of the Warburg effect enable PET scans to identify malignant tumors?

A

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

31
Q

In receptor mediated signaling: intracellular receptors are ____ ____ that are activated by ____-soluble ligands that can easily cross the plasma membrane.

A

transcription factors; lipid

32
Q

Vitamin D and steroid hormones are hydrophobic ligands that activate what kind of intracellular receptors?

A

nuclear hormone receptors

these are what normally bind estrogens and androgens for growth, important in cancers

33
Q

What are 4 activities that can result from EC binding of a receptor ligand?

A
  1. opening of ion channels
  2. activate associated GTP-binding regulatory protein (G protein)
  3. activate endogenous or associated enzyme (often tyrosine kinase)
  4. trigger proteolytic event or a change in protein binding or stability that activates a latent transcription factor
34
Q

Describe the non-receptor tyrosine kinase signaling pathway.

A

TM receptor binds EC ligand and IC an associated kinase phosphoylates the receptor for subsequent function

35
Q

Describe the receptor tyrosine kinase signaling pathway.

A

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

36
Q

Describe the GPCR signaling pathway.

A

ligand binds EC; the 7 TM domain receptor bound to heterotrimeric G proteins ultimately influences conversion of ATP–>cAMP

37
Q

Describe the nuclear receptor signaling pathway.

A

an IC receptor binds nuclear hormone that comes into the cell; together the receptor-ligand complex translocates to the nucleus and influences transcripton

38
Q

Describe the Notch signaling pathway.

A

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

39
Q

Describe the Wnt/frizzled signaling pathway.

A

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

40
Q

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?

A

augmented proliferative signaling, and cancer

41
Q

Alterations in tyrosine kinase receptor geometry can have what effect?

A

elicit intrinsic receptor protein kinase activity, or promote the enzymatic activity of recruited IC kinases, which results in downstream phosphorylation

42
Q

True or False: tyrosine kinase inhibitors are important in cancer treatment.

A

True

43
Q

What do each of these drugs do, and what cancers are they typically used for?:
Imatinib
Erlotinib
Sunitinib

A

Imatinib–inhibits tyrosine kinase in chronic myelogenous leukemia
Erlotinib–inhibits tyrosine kinase in some lung cancers
Sunitinib–inhibits tyrosine kinase in some kidney cancers

44
Q

Tyrosine kinase inhibitors given to treat cancer are taken ____ and are generally much ____ toxic than cytotoxic chemotherapy.

A

orally; less

45
Q

When GPCRs are bound by EC ligand, what happens with respect to GDP/GTP?

A

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.

46
Q

Wnt pathway involves the ____ family of TM receptors, which regulate IC levels of ____.

A

Frizzled; beta-catenin

47
Q

Normally, beta-catenin is constantly targeted for ____-directed proteasome degradation..

A

ubiquitin

48
Q

When Wnt binds to Frizzled, another IC protein called ____ is recruited that leads to disruption of the ________ complex.

A

Disheveled; beta-catenin degradation-targeting complex

49
Q

Wnt/Frizzled/beta-catenin pathway is important in what type of cancer?

A

colon cancer

50
Q

MYC and JUN are transcription factors that regulate the expression of genes for what?

A

cell growth

51
Q

Where do most transcription factors bind?

A

in long-range regulatory elements such as enhancers; enhancers are usually located nearby to genes but are sometimes far away

52
Q

For a transcription factor to induce transcription, it must also possess protein:protein interaction domains that do what?

A

directly or indirectly recruit:

histone modifying enzymes, chromatin remodeling complexes, and RNA polymerase

53
Q

Growth factor activity is mediated through binding to specific receptors, ultimately influencing the expression of genes that can do what?

A
  • 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)
54
Q

What are the two periods at which growth factors are involved in the proliferation of cells?

A
  • at steady state (for labile cells)

- after injury

55
Q

Many growth factor pathways genes are proto-oncogenes. This means what?

A

means that gain-of-function mutations in these genes can convert them into oncogenes capable of driving unfettered cell proliferation and tumor formation

56
Q

Describe the epidermal growth factor receptor family (EGFR).

A

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)

57
Q

The ____ receptor is overexpressed in a subset of breast (and other) cancers.

A

ERB-B2 (aka HER2)

58
Q

What do the drugs Trastuzumab and Pertuzumab do?

A

they are both antibodies against the ERB-B2/HER2 receptors; Trastuzumab prevents ligand-independent signaling while Pertuzumab inhibits ligand-dependent signaling; both activate ADCC

59
Q

True or false: cancers usually have a polyclonal origin.

A

False - cancers usually have a monoclonal origin; they arise from a single abnormal cell

60
Q

What two heritable properties define cancer cells?

A
  1. they reporduce in defiance of the normal restraints on cell division
  2. thy invade and colonize territories normally reserved for other cells
61
Q

Cancers develop in stages via ____ ____.

A 
clonal evolution; such as:
normal
-->low-grade intraepithelial neoplasia
-->high-grade intraepithelial neoplasia
-->invasive carcinoma
62
Q

General properties involved with converting cells to cancer cells include:

A
  • 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)
63
Q

What are oncogenes?

A

genes that act in a dominant fashion to stimulate or sustain replication; the mutation here that causes cancer is a “gain of function” mutation

64
Q

What are tumor suppressor genes?

A

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

65
Q

Proto-oncogenes can become oncogenic via what 4 ways?

A
  1. coding sequence mutation that makes normal amounts but of a hyperactive protein
  2. gene amplification to overproduce normal protein
  3. chromosome rearrangement to overproduce normal protein
  4. chromosome rearrangement resulting in hyperactive or overproduced fusion protein
66
Q

What are the two classifications of tumor suppressor genes, and how do they regulate?

A
  • gatekeepers - directly regulate cell growth

- caretakers - repair DNA damage, maintain genomic integrity

67
Q

True or false: it takes mutations in both proto-oncogenes to cause cancer, but only one mutation in a tumor suppressor gene.

A

False: it takes mutations in both tumor suppressor genes to cause cancer, but only one mutation in a proto-oncogene.

68
Q

The lymphatic pattern of metastatic spread is typical of ____.

A

carcinomas (cancer from epithelium or organ lining)

69
Q

The hemtogenous (to lung/liver) pattern of metastatic spread is typical of ____.

A

sarcomas (tumor of connective tissue or non-epithelium)

70
Q

The seeding (of body cavities/surfaces) pattern of metastatic spread is typical of ____.

A

ovarian carcinoma

71
Q

Describe the essential differences between oncogenes and tumor suppressor genes.

A

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.

72
Q

What type of molecular test/study would provide good evidence that proliferating cells are neoplastic?

A

a test showing that the cells all share some oncogene or tumor suppressor gene mutation(s)

73
Q

Metastatic ovarian carcinoma characteristically causes ____ ____ which could present as nausea and vomiting.

A

intestinal obstruction

cmod/pcm- block 2 (41 decks)

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