Basic Science > Cell Signaling Pathways > Flashcards
Cell Signaling Pathways Flashcards
Toceranib phosphate blocks which receptors?
VEGF-R2
PDGF-R alpha/beta
KIT
FLT3
Masitinib blocks which receptors?
PDGF-R alpha/beta
KIT
Down regulation of what receptor is associated with worse prognosis for canine meningiomas?
Progesterone receptor
What kind of kinases are CDKs? (Phosphorylate what residues?)
Serine/threonine
In what phase of the cell cycle are levels of cyclin B highest?
Raise in anticipation and during M phase.
In what phase of the cell cycle are levels of cyclin D1 highest?
G1
In what phase of the cell cycle are levels of cyclin E highest?
Rise at end of G1, fall after R point and during S.
In what phase of the cell cycle are levels of cyclin A highest?
S phase
Does TGF-beta antagonize or facilitate cell proliferation and differentiation?
Antagonize
During what phase of the cell cycle is pRb hypophosphorylated?
G1 up till the restriction point
What are the initiator caspases in apoptosis (name 2)?
8 and 9
What are the effector caspases in apoptosis (name 3)?
3, 6, and 7
Pro-apoptotic or anti-apoptotic: Bcl-2?
anti
Pro-apoptotic or anti-apoptotic: Bax?
pro
Pro-apoptotic or anti-apoptotic: BAD?
pro
Pro-apoptotic or anti-apoptotic: BIM?
pro
Pro-apoptotic or anti-apoptotic: BCLXS?
pro
Pro-apoptotic or anti-apoptotic: BAK?
pro
Pro-apoptotic or anti-apoptotic: BOK?
pro
Pro-apoptotic or anti-apoptotic: BCLXL?
anti
Pro-apoptotic or anti-apoptotic: BCLW?
anti
Which of the following are involved in inhibition of cyclin B activity?
i. MYT1 kinase
ii. D3A kinase
iii. WEE1 kinase
iv. KIP1
a. i, iii, iv
b. ii, iv
c. i, ii
d. ii, iii, iv
a: MYT1, WEE1, KIP1
Explanation: p. 197 fig. 9-4, also text on p. 198 and 202. MYT1 and WEE1 phosphorylate CDKs that are cyclin-bound, which inactivates the CDKs. KIP1 can also inhibit CDKs by binding them. D3A is made up.
Choose the correct pairing of cyclin(s) and cyclin dependent kinase(s).
a. CDK1 – Cyclin E and Cyclin A
b. CDK2 – Cyclin C
c. CDK3 and CDK5 – Cyclin A and Cyclin B
d. CDK4 and CDK6 - Cyclin D
d - CDK4/6 and Cyclin D
Explanation: p. 198 and figure 9.5. CDK1 goes with A and B. CDK2 goes with E and A (cyclin C is made up). CDKs 3 and 5, are made up (actually, they probably exist but are not mentioned in text).
Which of the following could promote tumor development?
a. Increased activity of p16INK4A
b. A mis-sense mutation in the gene for Cyclin D1
c. Decreased activity of the E2F transcriptional program
d. An amino acid substitution that promotes binding of Cyclin B to CDK1
d - AA substitution promoting binding of CDK1-cyclin B
Explanation: (a) p16INK4A is an inhibitor of G1/S transition; increased activity would make it harder to proceed through the cell cycle. (b) Cyclin D1 is also required for G1/S transition, so an inactive gene product will make it harder to proceed through cell cycle. (c) The E2F transcriptional program codes for Cyclin E, Cyclin A2, and EMI1, which help reverse the inactivity of CDK1 and CKD2 in G1. (d) The Cyclin B/CDK1 complex facilitates transition from G2-> M; increased binding should make this more likely.
Which of the following conditions occur during G1-phase to allow for pre-RC assembly?
a. High levels of Cyclin A2 and B
b. Absence of CDK1 and CDK2 kinase paired with high APC/CCDH1 activity
c. High levels of the F-box protein, SKP2
d. Absence of Cyclin D-CDK4/6 activity
e. Increased Cyclin A2-CDK2 and Cyclin E-CDK2 activity
b - absence of CDK1/2 with high APC/CCDH1
Explanation: T&H, pages 199-201. The “first state” of the cell cycle lasts from anaphase to the end of the next G1-phase. Pre-RCs are assembled during G1-phase and fire during S-phase; the separation between these activities helps ensure there is only one replication per cycle. During this time, CDK1 and CDK2 kinases are absent and APC/CCDH1 activity is high – these conditions allow for pre-RC assembly on replication origins. During the second state of the cell cycle, the reverse is true: CDK2 activity is high and APC/CCDH1 activity is low. Distractors: a) Cyclin A2 and B levels are very low because they are substrates of APC/CCDH1. c) APC/CCDH1 targets SKP2 for degradation. d) Cyclin D-CDK4/6 activity is relatively constant, but is decreased during G0-phase. This complex also plays several roles during the G1/S transition. e) The rise of Cyclin A2-CDK2 and Cyclin E-CDK2 occurs during the G1/S transition, and triggers DNA replication.
What compound is responsible for communication between the death receptor and mitochondrial apoptotic pathways?
a. CASP8
b. cFLIP
c. CASP11
d. APAF-1
e. c-IAP2
a - Caspase 8
Explanation: CASP8 is involved in the death receptor pathway. However, when it cleaves BID, this causes BID (specifically tBID, the cleaved version) to interact with BAX. Openings are formed on the mitochondrial membrane, leading to release of cytochrome C, SMAC and OMI, all of which are involved in the mitochondrial pathway. Distractors: b) cFLIP is an inhibitor of the death receptor pathway; it prevents binding of CASP8 to DISC. c) Not involved in either pathway (to my knowledge), but plays an important role in inflammation. d) Part of the mitochondrial pathway; binding of cytochrome C to APAF-1 leads to formation of the apoptosome. e) IAP = inhibitor of apoptosis; self-explanatory.
An increase in what compound(s) triggers the events of early mitosis?
a. APC/CCDH1
b. Cyclin D-CDK4/6
c. Cyclin A2-CDK2 and Cyclin E-CDK2
d. Cyclin B-CDK1
e. WEE1 and MYT1
d - Cyclin B - CDK1
Explanation: The early events of mitosis are governed by the following kinases: Cyclin B-CDK1, PLK1, AUR A and AUR B. A surge in Cyclin B-CDK1 is what initiates early mitosis. Distractors: a) High during G1-phase to allow for pre-RC assembly; b) Active during G1/S transition. c) Also active during G1/S transition to trigger DNA replication. e) While WEE1 and MYT1 are involved in mitosis, Cyclin B-CDK1 serves to inactivate these factors. If they are elevated, they will phosphorylate CDK1 and stop Cyclin B-CDK1 kinase activity.
During which cell cycle phase is CDK2 (cyclin dependent kinase-2) activity the lowest?
a. Mitosis
b. G1
c. S
d. G2
b. - G1
Explanation: p 199 T&H. During G1 phase both CDK1 and CDK2 are not bound to CYCLINs and their kinase activity is low. CDK1 forms complexes with CYCLIN A and CYCLIN B, both of which have low levels during G1 phase (substrates of APC/C, which is active during G1). CDK2 forms complexes with CYCLIN A and CYCLIN E. p27 is indirectly stabilized by APC/C, allowing p27 to bind to and inactivate CYCLIN B-CDK1 and CYCLIN A2-CDK2 complexes.
Which of the following statements is true regarding the restriction point of the cell cycle?
a. Transition through the restriction point is governed by p53
b. Cellular transition through the R point is irreversible
c. Cells must pass through the restriction point to leave G0
d. The molecular basis for the restriction point is the switch from high to low CDK2 activity and low to high APC/CCDH1 activity
b. - Transition through R is irreversible
Explanation: If cells do not have sufficient nutrients, growth factors they may die, but if cells do not die a transition in G1 phase (restriction point) determines the cellular response. If GFs are withdrawn prior to R point, cells will enter G0 state. If the factors are withdrawn after R point cells will progress through a full cell cycle before transitioning into the G0 state. The R point can occur late or early during G1 phase of the cell cycle (depends on the type of cell). In most cancers, the control over the R point becomes loosened. The molecular basis for the R point is the switch from LOW to HIGH CDK2 and HIGH to LOW APC/CCDH1 activity.
A drug targeting Polo-like Kinase 1 (PLK1) will target cells in which phase of the cell cycle?
a. G1
b. S
c. G2
d. M
d. - M phase
Explanation: PLK1 is one of the 4 kinases that is responsible for orchestrating events in early mitosis. The other three are CYCLIN B-CDK1, AUR A, and AUR B. Targeting these 4 kinases should theoretically spare quiescent cells.
Recovery from mitosis and progression to the S phase of the cell cycle is characterized by:
i. increase in APC/CCDH1 ii. decrease in APC/CCDH1 iii. increases in CDK1 and CDK2 iv. decreases in CDK1 and CDK2 v. pre-RC assembly performed vi. pre-RC assembly ubiquination
a. i, iii, v
b. I, iv, vi
c. ii, iii, v
d. ii, iv, vi
e. i, iv, v
E - incr in APC/CCDH1, decr in CDK1 and CDK2, pre-RC assembly performed
Source: page 199 Tannock , The first phase of the cell cycle progression is characterized by high APC/CCDH1, low CDK1 and CDK2, pre-RC assembly.
c-MYC-induced tumorogenesis is associated with overexpression of:
a. FAS b. BAX c. PUMA d. BCL-XL e. CASP9
D - BCL-XL
Source: page 215
What is the primary defect detected by the spindle assembly checkpoint?
a. presence of three kinetochores
b. kinetochores that are not attached to microtubules
c. ubiquitination of Securin
d. properly bi-oriented chromatids
e. increased levels of tension between centromeres
B - kinetochores that are not attached to microtubules
page 206
Identify which protein complex is responsible for the segregation of the 2 sister chromatids into separate daughter cells during mitosis. This complex is also important for the repair of dsDNA breaks by recombination between sister chromatids.
a. Polo-like kinase 1
b. Cohesin
c. CuL4-DDB1
d. APAF-1
b - Cohesin
Explanation: p. 202 and also p. 204
During anaphase, once Cohesin is completely removed, the sister chromatids are free to respond to the pulling forces exerted on their kinetochores and progress toward opposite spindle poles.
PLK1= Polo-like kinase 1 is one of the 4 mitotic kinases that helps orchestrate the events of early mitosis
CuL4-DDB1= is one of three E3 ligases with important cell cycle roles
APAF-1= apoptosis protease activating factor plays a critical role in the intrinsic apoptotic pathway
Identify the correct match up for the morphological changes that occur during apoptosis vs. necrosis.
a. Necrosis= rounding up of the cell, plasma membrane blebbing
b. Apoptosis= disintegration of all cellular components and inflammation
c. Necrosis= cytoplasm shrinkage, alteration of membrane asymmetry
d. Apoptosis= fragmentation into cellular bodies, elimination by phagocytosis
D. Apoptosis= fragmentation into cellular bodies, elimination by phagocytosis
Explanation: p. 208. Changes associated with apoptosis include rounding up of the cell, plasma membrane blebbing, cytoplasm shrinkage, alteration of the membrane symmetry, condensation and fragmentation of the nucleus. Cells at late stages of apoptosis become fragmented into apoptotic bodies that are eliminated by phagocytic cells without triggering inflammation.
Necrosis-associated cellular changes are manifested by swelling of the cell, mitochondria and cytoplasmic organelles, followed by focal rupture of the plasma membrane. Moderate chromatin condensation is also displayed by necrotic cells. More advanced stages of necrosis are associated with disintegration of all cellular components and inflammation.
Identify the type(s) of errors that occur during cell proliferation that is often clinically detected as a common feature of many types of cancer.
i. Aneuploidy
ii. Extra centrosomes
iii. Homologous recombination leading to genomic instability
iv. Chromosome instability
a. i, ii, iii, iv
b. iii, iv
c. i, ii, iv
d. ii, ii, iv
C. Anuploidy, extra centrosomes, chromosome instabil.
Explanation: p. 206-207
Aneuploidy occurs from wholesale changes in the number of chromosomes which presumably arise from errors in mitosis. Aneuploidy that results from mitotic errors can be a cause of cancer. More than 90% of clinically detected solid tumors are aneuploid.
Chromosome instability is the failure to properly segregate 1 copy of the sister chromatid pairs to each of the 2 daughter cells, a failure that results in 2 aneuploid daughter cells. In some cancer cell lines, chromosomes can be missegregated nearly every cell cycle.
Cell cycle defects that weaken the blocks against centriole rereplication appear to arise during the evolution of many cancers. At the start of mitosis, the presence of extra centrosomes results in spindle with more than 2 poles.
Does PTEN inhibit or activate the PI3K/AKT pathway?
It inhibits
A major negative regulator of the PI3K pathway is:
a. PTEN b. RON c. MAPK d. TORC e. EGFR
A - PTEN
page 180
Which of the following is TRUE regarding TGF-β?
a. TGF-β functions solely as a tumor suppressor gene
b. the downstream effects of TGF-β are mediated through SMURF proteins
c. TGF-β must be dimerized before becoming biologically active
d. After TGF-β binding, the type II receptor phosphorylates to create downstream effects
e. SMAD proteins regulate ubiquitination of TGF-β
C - TGF-β must be dimerized before becoming biologically active
Page 189
Explanation: a) can be both TSG and oncogenes B) the biologic activity is primarily through the type I receptor of the TGF-β complex D) the type I receptor also is the one that phosphorylates E) SMURF proteins regulate the ubiquitination of the SMAD proteins
Which of the following are TRUE regarding RAS proteins:
i. The only downstream effectors are RAF and PI3K ii. RAS are GTPases that cycle between on and off in response to extracellular signals iii. Newly synthesized RAS must undergo post-translational modification to be active iv. the most common mutation in canines is N-ras v. hydrolysis of the activated RAS-GTP complex is performed by GTPase-activating proteins (GAPs)
a. i ii, iii
b. i, ii, iv
c. i, ii, v
d. ii, iii, iv
e. ii, iii, iv, v
E - ii, iii, iv, v
page 177-178
Explanation: i) also includes RALGDS
Which of the following is/are TRUE regarding the function of tyrosine kinases?
i. The extracellular domain frequently undergoes posttranslational modification by hydroxylation.
ii. The extra- and intracellular domains are connected by a hydrophilic transmembrane component.
iii. The catalytic intracellular domain is highly conserved.
iv. Phosphorylation frequently occurs in the juxtamembrane region.
v. Phosphorylation in catalytic regions creates in docking sites for downstream signaling molecules.
a. i, ii, iv
b. iii, iv
c. ii, iv, v
d. ii, iii, v
e. i, iii
b - The catalytic intracellular domain is highly conserved; Phosphorylation frequently occurs in the juxtamembrane region.
Explanation: T&H, pages 174-5. False explanations - i) Posttranslational modification is most frequently via glycosylation. ii) The transmembrane component is hydrophobic. v) Phosphorylation of noncatalytic regions creates docking sites. Phosphorylated catalytic sites allows access to ATP and protein substrates.
What is the key mediator of the canonical WNT signaling pathway?
a. AXIN
b. APC
c. GSK3
d. β-catenin
e. DSH
d - β-catenin
Explanation: T&H, page 185. The WNT signaling cascade results in β-catenin stabilization/accumulation, entry into the nucleus, and regulation of gene transcription. In the absence of β-catenin, transcription of WNT target genes is repressed.
Which of the following signaling pathways first requires processing by the Golgi apparatus prior to docking on the cell membrane?
a. NOTCH
b. N-RAS
c. Janus kinase
d. WNT
e. PI3K
a - Notch
Explanation: T&H, page 186. The Notch signaling pathway involves three cleavage events that occur during receptor maturation and signal transmission. 1) NOTCH is processed into 2 fragments by the Golgi. 2) NOTCH binds to ligands on neighboring cells, which causes a second cleavage to release the extracellular domain. 3) The γ-secretase complex causes the final cleavage, releasing the active intracellular domain, NIC, which is translocated to the nucleus.
Identify the true statement in regards to the transcription factor DNA-binding domain classes?
a. Members of the homeodomain factors include the fos/jun pair (called the AP1 transcription factor) which becomes activated by cellular stress, proliferative and developmental stimuli
b. Leucine-zipper transcription factors contain a 60 amino-acid DNA-binding domain called a homeobox that contains 3 helical regions
c. Zinc finger transcription factors mediate differentiation and growth signals, including those caused by binding of steroid hormones to receptors
d. Transcription factors can only activate, and not repress, gene expression by binding to specific DNA recognition sequences
c - Zinc finger transcription factors mediate differentiation and growth signals, including those caused by binding of steroid hormones to receptors
Explanation: p. 180-181
a. Members of the leucine-zipper transcription factors include the fos/jun pair (called the AP1 transcription factor) which becomes activated by cellular stress, proliferative and developmental stimuli
b. Homeodomain transcription factors contain a 60 amino-acid DNA-binding domain called a homeobox that contains 3 helical regions
e. d. Transcription factors can activate and repress gene expression by binding to specific DNA recognition sequences
What is an important mechanism for suppression of growth factor signaling or termination in many cell signaling pathways?
a. Phosphorylation of proteins
b. Ubiquitination of proteins
c. Binding of zinc ions to protein domains
d. Activation of cellular integrins
b - Ubiquitination of proteins
p. 182
Explanation: modification of proteins with ubiquitin is an important mechanism for signal termination. Failure of ubiquitination of RPTKs can result in prolonged activation and oncogenic signaling.
What membrane receptor complex is associated with the hedgehog gene?
a. Patched and Smoothened receptors
b. Notch receptor
c. TORC1 and TORC2
d. Janus Kinase family of receptors
a - Patched and Smoothened receptors
p. 187-188
Explanation: The Hh gene products encode ligands that signal through a membrane receptor complex including the Patched (PTC1 and PTC2) and Smoothened (SMO) receptors, which together form a molecular switch controlling activation of downstream target genes.
Which of the following is a correct pairing of ligand with its receptor tyrosine kinase?
a. VEGF / PDGFR-beta
b. HGF / MET
c. FGF / ERBB2
d. TGF-alpha / TRKC
b. HGF/MET
Explanation: taken directly from Fig. 8.1 on p 174
Which of the following contributes to G1-S transition by complexing with its CDK, inactivating Rb, and releasing E2F transcription factor?
a. Cyclin A
b. Cyclin B
c. Cyclin D
d. Cyclin E
c - cyclin D
Explanation: pp 181-182, also revisited on pp 199-200.
Which of the following would be least affected by changes in the WNT signaling pathway?
a. c-myc
b. Frazzled
c. cyclin D1
d. metalloproteinase 7
Answer: b (frazzled)
Explanation: c-myc, cyclin D1, and MMP7 are all target genes of the WNT signaling pathway. P. 185. Frazzled does not exist.
Which of the following is a Pleckstrin homology (PH) domain containing protein kinases?
a. RAS
b. SOS
c. AKT
d. GRB2
c - AKT
Explanation: AKT and PDK1 are PH-domain containing protein kinases and are involved in the PI3K signaling pathway. Other domains that serve as binding sites for targets are SH2, SH3, and PTB (phosphotyrosine binding). GRB2 has SH2 and SH3 domains and p85 contains 2 SH2 domains.
Which of the following could be used to target TORC1 for therapeutic purposes?
a. Rapamycin
b. Bevacizumab
c. Farnesyltransferase inhibitors
d. Dasatinib
a - Rapamycin
Explanation: TORC1 and TORC2 are mTOR (mammalian target of Rapamycin) Complex 1 and 2, respectively. TORC1/2 are activated by AKT signaling. TORC1 controls a wide range of cellular processes that promote proliferation including protein synthesis through the phosphorylation of eukaryotic translation initiation factor binding protein (4E-BP1) and S6 kinase 1 (S6K1). TORC1 regulates ATP production and metabolism by promoting the expression of HIF1a that regulates the expression of glycolytic genes controlling glucose metabolism. Also it inhibits autophagy by phosphorylation and inhibition of the activity of ATG13.
Which of the following determines the specificity of ubiquitination of proteins?
a. ubiquitin-activating enzyme - E1
b. ubiquitin-conjugating enzyme - E2
c. ubiquitin ligase – E3
d. 26S proteasome
c. Ub ligase (E3)
Explanation: E3 ligase selectively binds substrates – specificity is determined by E3. E1 and E2 are involved in the initial steps of gathering free ubiquitin from cytoplasm prior to ubiquitination. Ubiquitinized proteins are degraded by the 26S proteasome.
