Receptors and Cell Signaling & Cell Cycle, Apoptosis, and Cancer

Question 1

Endocrine Signaling

Answer 1

Long distant signaling; goes to distant target cells
Signal –> bloodstream
Long lasting effects
Signal freely diffuses

Question 2

Paracrine signaling

Answer 2

Acts locally
Short lived signal
Ex. NT

Question 3

Autocrine signaling

Answer 3

Cells responds to signals that they themselves released
Cell secretes signal that feeds back on binds to own receptor
Ex. Growth factors in cancer cells

Question 4

Direct/Juxtacrine cell signaling

Answer 4

Where signal is brought directly to target cell
Ex. Immune cells
Ag-presenting cells to T cells

Question 5

Lipophillic molecules

Answer 5

Long half-lives (hrs - days)
Often taken daily
Bind to intracellular receptors

Ex. Ethinyl estradiol

Question 6

Hydrophillic molecules

Answer 6

Short half-lives (sec - min)
Administered when needed
Bind to extracellular receptors –> signal transduction
1) Change in activity/function of enzymes (fast)
2) Change in amounts of protein by change in expression of genes (slow)

Ex. Epinephrine

Question 7

Cholera toxin

Answer 7

Prevents activation of Gs-alpha subunit

• Covalently modifies (via ADP ribosylation) the alpha subunit of Gs.
• ADP ribosylation of an arginine residue on Gs-alpha decreases its intrinsic GTPase activity
• elevated cAMP –> opening Cl- channels –> loss of water and electrolytes

Question 8

Pertussis toxin

Answer 8

Prevent activation of Gi-alpha subunit

• ADP ribosylation of a cysteine residue on Gi-protein prevents activation and dissociation of its subunit from the trimeric G protein
• Result: less inhibition of adenylate cyclase and overproduction of cAMP
• In airway epithelial cells, pertussis toxin causes loss of fluids and excessive mucous secretion –> whooping cough

Question 9

Desensitization of signal

Answer 9

Remove signaling molecule: phosphodiesterases will remove cAMP/cGMP

Receptor sequestration: endosome

Receptor desctruction: endosomes + lysosomes (proteases)

Question 10

GRK

Answer 10

G protein receptor kinases phosphorylate receptor and recruits arrestin

Arrestin binds to 3rd loop and prevents Ga from interacting with 3rd loop
Result: G-alpha GDP doesn’t get converted to G-alpha GTP

Question 11

Phosphodiesterases

Answer 11

Breakdown cAMP and cGMP

Question 12

Oncogenes

Answer 12

Promote cell proliferation
src
erb
ras

Inhibit apotosis
bcl-2

Question 13

Tumor suppressor genes

Answer 13

Inhibit cell proliferation
apc
rb

Promote apotosis
p53
BRCA1
BRCA2

Question 14

Cyclins in G1

Answer 14

Cyclin D - CDKs 4 and 6

Question 15

Cyclins in G1 –> S transition

Answer 15

Cyclin E - CDK2

Question 16

Cyclins in S

Answer 16

Cyclin A - CDK2 activation to induce enzymes necessary for DNA synthesis

Question 17

Mitosis

Answer 17

Cyclin A -CDK1 and Cyclin B -CDK1

Question 18

CIP/KIP family of CKIs

Answer 18

CKIs bind to G1 and S phase cyclin-CDK complexes to activate the kinase activity of CDK
-Eventually degraded

Question 19

INK4 family of CKIs

Answer 19

Bind specifically to G1 CDKs

-Prevents them from associating with cyclin D

Question 20

Wee1 Kinase

Answer 20

Phosphorylates roof site of CDK to inhibit cyclin and CDK association

Inactivates CDK

Question 21

Cdc25 phosphatase

Answer 21

Dephosphorylates the roof site of CDK to allow activation and association with cyclin.

Activates CDK

Question 22

APC/C

Answer 22

Targets S-cyclins and M-cyclins
Cyclins destroyed
Inactivates most CDKs
CDKs dephosphorylated
Needed for cell to move to anaphase
-Must get rid of s-cyclin and m-cyclin

Question 23

Cdc20

Answer 23

Activates APC/C

Question 24

p53

Answer 24

Tumor suppressor gene
TF
Stabilized by phosphorylation

Active p53 leads to transcription of CKI (p21)
p21 binds and inactivates cyclin-CDK complexes –> cell cycle arrest

Question 25

MDM2

Answer 25

Keeps p53 inactive

An E3 ubiquitin ligase that keeps p53 inactive through degradation

Question 26

p21

Answer 26

p53 –> transcription of p21
p21 binds and inactivates cyclin-CDK complexes –> cell cycle arrest

Cyclin E-CDK2 (G1 –> S phase transition) and Cyclin A-CDK2 (S phase transition) targets of p21

Question 27

BAX

Answer 27

Stim. release of cyt C from Mito

Activates intrinsic pathway of apotosis

Question 28

Bcl-2

Answer 28

Inhibits cyt C release from Mito
Inhibits intrinsic pathway of apotosis
Inhibits aggregation of APAF-1 –> inhibition of Caspase-9

Question 29

Ras

Answer 29

Proto-oncogene
Point mutation at codon 12 gly –> val

Result: Ras oncoprotein occurs ~25% cancers

Question 30

HER2

Answer 30

Proto-oncogene
Member of the family of EGF receptors (RTKS)
Point mutation val –> gln

Result: Oncoprotein NEU observed in some breast cancers

Amplification
Result: overexpression of HER2 & observed in many breast cancers

Question 31

EGF receptor

Answer 31

Proto-oncogene
Deletion in part of a gene

Result: oncoprotein EGFRvIII lacks the extracellular ligand-binding domain and constitutively signals in the absence of ligand
Glioblastoma

Question 32

N-Myc

Answer 32

Proto-oncogene
Amplification

Result: Elevated levels N-Myc transcription factor observed in neuroblastoma

Question 33

c-Myc

Answer 33

Proto-oncogene
Chromosomal translocation

Reciprocal translocation b/w chr 8 and 14

Result: MYC TF overexpressed because translocation puts c-Myc under the influence of the immunoglobulin heavy-chain gene enhancer

Observed in Burkitt lymphoma

Question 34

ABL

Answer 34

Proto-oncogene
Translocation b/w chr 9 and 22, which generates a derivative of chromosome 22 known as Philadelphia chromosome

Result: Generates the BCR-ABL fusion oncoprotein (an unregulated protein tyrosine kinase) because the translocation creates a BCR-ABL fusion gene

Creates chromic myelogenous leukemia (CML)

Question 35

Herceptin

Answer 35

Inhibits HER2 receptor & NEU

Question 36

Erbitux

Answer 36

Inhibits EGF receptor

Question 37

Gleevec (imatinib)

Answer 37

Inhibits BCR-ABL fusion protein