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75 Cards in this Set
- Front
- Back
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Covalent/Non-Covalent molecular interactions are responsible for biological specificity.
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Non-Covalent
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Put in order of function:
Receptor Metabolic Response Effector Ligand Transcription Factor Transducer Second Messenger Protein Kinase |
Ligand-Receptor-Transducer-Effector-Second Messenger-Protein Kinase-Transcription Factors-Metabolic Response
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Explain the study of saturation kinetics, understand the graphs on page 165 (I think it's smart to understand the assay that gives this graphical info).
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Saturation kinetics is the study of affinity for a substrate to its target, in this case a ligand for a receptor. Binding is extremely specific so the graphical analysis reflects a substrate and its analogs (done under physiological conditions). Initial graph is hyperbolic, but further manipulation gives Vmax and Km. Total Binding- bound ligand without washing. Specific Binding- bound ligand with washing. Nonspecific Binding- What would bind to the plate or elsewhere nonspecifically and after washing.
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What is unique about nuclear receptors that is different from other cell receptors?
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A unique property of nuclear receptors which differentiate them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA-- they actually bind to DNA.
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What are some examples of ligands that act on nuclear receptors? What is unique about them that is different from other cellular ligands?
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Steroids
Thyroid Hormones Retinoids Vitamin D They can cross the cellular membrane and go straight to the nucleus of the cell-- this is due to their hydrophobic nature. Note that other ligands stay on the outside of the cell and do not cross to cause a signal cascade. |
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What are the four main examples of steroid hormones?
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estrogens
androgens progesterone glucocorticoids |
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Carried in the blood bound to ___ due to their ___.
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Carried in the blood bound to specific carriers due to their insolubility. Hydrophobic molecules.
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How do they enter the cell and does it require energy?
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Simple diffusion; no plasma membrane receptor and no energy required.
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Where do they bind to their high affinity receptor?
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Two different types (according to Derek T. Moore)
Top of 166- Nucleus of the cell Picture on 166- cytosol of cell; then the complex moves into nucleus **Either way, I think you get the idea. |
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What is unique about a steroid binding protein, i.e. what other sites does this molecule have?
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DNA-binding region which forms metal-binding fingers (zinc fingers).
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Look over the steps of steroid hormones on page 166.
What do steroid hormone-receptor complexes bind to? And what do they influence? Are they direct or indirect? |
Bind to DNA and influence mRNA synthesis (transcription); Direct influence
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Steroid receptors can be acted on by drug targets. Explain the action of tamoxifen.
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Tamoxifen is an estradiol analog. It inhibits the action of estradiol by competitively binding the estrogen receptor. Used in treatment of breast cancer.
Extra info: Some breast cancers, specifically HER1&2 type are "fueled" by estrogen, so by blocking them you can slow or stop tumor growth. |
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Thyroid hormones are another example of ligands that bind to nuclear receptors. What special secondary structure do they have? What do they induce synthesis of?
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Zinc Finger; they increase specific RNA; inducing new Na+K+ATPase
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Retinoids have what DNA binding domain?
Note: They are related to Vitamin A; regulate epithelial cell growth. |
Zinc Finger
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Vitamin D3. Binds nuclear receptor in ___, ___, and ___.
Activates genes encoding ___ binding proteins including ___. |
Vitamin D3. Binds nuclear receptor in intestine, bone, and kidney. The intestine "soak up" Ca++ that is used in bone growth. Deficiency = rickets.
Activates genes encoding Ca binding proteins including Ca ATPase. |
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What are the major classes of plasma membrane receptor ligands?
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Peptides
Catecholamines-neurotransmitters Prostaglandins/Leukotrienes |
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Give a brief overview of Adenylate cyclase rxn. Practice drawing it out.
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Ligand binds receptor. G protein activated. G protein activates adenylate cyclase. Adenylate cyclase converts ATP into cAMP. Signal amplified at each step.
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cAMP is turned off by what?
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Phosphodiesterase hydrolyzes cAMP into AMP.
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Phosphodiesterase is activated by what?
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Ca+ Calmodulin
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Phosphodiesterase is inhibited by what?
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Caffeine and theophylline
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The G protein is active when bound to GTP or GDP?
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GTP
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The G protein has several subunits, which subunit is it bound to GTP and acts as the activated form?
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alpha subunit binds the GTP and acts on the adenylate cyclase. The beta and gamma subunits it breaks off of in the active form.
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What hydrolyzes the bound GTP back to GDP terminating the cyclase activation?
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Intrinsic GTPase
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What analog greatly increases adenylate cyclase activity?
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Nonhydrolyzable GTP analogs (GppNHp)
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One type of signal, Beta-Adrenergic amines activate the adenylate cyclase through which G type?
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Gs (page 172)
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Beta-Adrenergic receptor is deactivated by what?
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Phosphorylation of the HORMONE-RECEPTOR complex (not receptor alone) is done by a B-AR kinase. After phosphorylation B-arrestin binds and blocks. G cannot work.
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cAMP activates what?
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PKA (dissociates the R subunits from the C subunits).
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What are some examples of the things that PKA regulates?
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Glycogen breakdown (remember it's used in the glucagon state NOT insulin state)
Cl- activation Phosphorylation of CREB (for promotion of transcription) More examples pg 173 |
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These target proteins can be switched off by what?
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Dephosphorylation by phosphoprotein phosphatases
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Note: We are done discussing adenylate cyclase cascade. This is the second cascade in the syllabus.
What G protein type activates the phospholipase C and phosphoinositide cascade? |
Gq (and not the stud mgz.) table page 172
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Phosphatidyl inositol is activated by phosphorylation into PIP2 which triggers phosphlipase C to produce which two second messengers?
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IP3 and Diacylglycerol
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What does IP3 do?
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Rapid release of Ca++ from SR and ER. IP3 actually binds receptors in the ER membrane.
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What does diacylglycerol do?
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Activates protein kinase C. This increases its affinity for Ca++ and activates it according to the physiological Ca++ levels.
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Protein kinase C requires several things for full activation. What are they? Hint pg 175.
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Phosphorylated (at Ser and Thr residues)
Ca++ Diacylglycerol Bound to membrane |
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How is this cascade turned off? There are at least four major ways.
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GTPase inactives Gq (intrinsic)
Ca++ pumped back into ER/SR or out of cell (know the ATPases responsible) Diacylglycerol and IP3 are recycled to phosphatidyl inositol Protein phosphatases dephosphorylate target proteins |
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What is the big example of a hormone that works via the phosphoinositide cascade?
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GnRH; it follows the cascade releasing Ca++ and activating specific proteins that eventually cause FSH and LH to release in the anterior pituitary cells.
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What occurs when epinephrine binds to an alpha receptor in liver? Hint: uses phosphoinositide cascade, and is review from Block II.
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Epinephrin binds leading to activation of Phospolipase C. Phospho C hydrolyzes PIP2 into DAG and IP3. IP3 releases Ca++ from ER; the Ca++ and DAG stimulate protein kinase C. Protein kinase C phosphorylates glycogen synthase (inactivate because you are not building; you are breaking down-- hunger state)
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Colmodulin undergoes ___ when it binds Ca++ with high affinity?
Note: the Ca++ calmodulin complex activates phosphorylase kinase which phosphorylates glycogen phosphorylase a, activating that at the same time as protein kinase C is active. |
Conformational change-- activates
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What are some examples of the things Ca++ Calmodulin activates?
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myosin light chain kinase
cAMP phosphodiesterase Ca++ ATPase phospholipase A2 Cam Kinase |
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What are three examples of receptors that use tyrosine kinase activation?
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Insulin receptor
EGF receptor PDGF receptor |
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Tyrosine kinase receptors phosphorylate themselves as well as the secondary messengers. Insulin is the major example used in the syllabus. What are the chief targets of insulin?
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Muscle, liver, and adipose
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What does insulin increase production of?
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GLUT4 transporters; which transport glucose
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Where does insulin bind on the insulin binding receptor?
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The alpha subunit
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Where on the insulin binding receptor is the tyrosine kinase activity?
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Beta subunits
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When the insulin receptor autophosphorylates via the tyrosine kinase activity it leads to activation of more than one downstream signaling pathway. BOTH kinases and phosphatases are activated. What transmits the signal to downstream protein kinases (MAP cascade)?
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Small G proteins
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Small G proteins are active when bound to what?
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GTP
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What are two major examples of small G proteins?
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ras and rho
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ras and rho are activated by what?
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binding of sos; results in switch to GTP
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Active ras activates what downstream?
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protein kinase(s)
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What inactivtes the small G proteins?
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intrinsic GTPase
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They can be bound to membrane or free in the cytosol.
What anchors small G proteins to the membrane? |
Isoprenoid groups
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What inhibits isoprenylation of signaling molecules such as ras, rho, and rac?
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dual activity of statins (page 181)
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How is the insulin signal switched off (besides GTPase activity of small G proteins and phosphoprotein phosphatases)?
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Endocytosis of insulin-receptor complex. Inclusion into vesicles which will ultimately fuse with lysosomes.
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What coats the vesicle?
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Clathrin forms lattice around the pit. Forms endosome.
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RECAP: Tyrosine Kinase receptors include insulin and two other examples. Name them.
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EGF- Epidermal Growth Factor
PDGF- Platelet Derived Growth Factor BONUS! NGF- Nerve Growth Factor NOTE- Similar cascade events as insulin and receptor-hormone complex endocytosis to decrease the signal. |
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Growth Hormone is inactive as a monomer/dimer?
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monomer
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What is associated with the monomeric growth hormone?
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inactive tyrosine kinase; JAK2
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How is JAK2 activated?
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After hormone binds and dimerizes the JAK2 gets cross phosphorylated.
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What does JAK2 specifically activate?
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STAT5
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Read the excellent summary of plasma membrane receptors on page 183.
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Hormone doesn't have to enter cell
Signal amplified at each step Signal is transient, and can be switched off at every level Cancer cells lose ability to turn off signal Protein kinases regulate key cell functions |
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Cholera toxin.
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Stimulates adenylate cyclase activity in intestine. G protein is locked in active GTP state by blocking GTPase. Elevated cAMP which activates CFTR via PKA-phosphorylation. Unregulated salt and water excretion.
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Pertussis toxin.
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Inhibits adenylate cyclase by stabilizing the GDP form of the G protein.
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Diptheria toxin.
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ADP-ribosylation of elongation factor-2 (EF2). Stops protein synthesis by preventing translocation step.
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Anthrax toxin.
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Edema factor (EF) is one protein of the complex. EF binds calmodulin. Calmodulin cannot function normally. EF now becomes an adenylate cyclase activity. Increased cAMP and blocking of inflammatory response in host defense.
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Oncogenes arise from normal what?
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Proto-oncogenes.
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What is a major example of a tumor suppressor gene?
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p53 (inactivation is one of the hits that leads to cancer)
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What are some major oncogenes?
Review page 187 and note these are talked about very frequently at MDACC and basic understanding of them is key to oncology. Also note summary on page 189. |
Tyrosine Kinases; c-src
G Protein Analogs; ras DNA Binding Proteins; c-myc Growth Factor Analogs; v-sis Hormone Receptor Analogs; c-erb and erb-A |
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What are the most variable phases of cell cycle?
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G1 and G2.
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What phases are absent in embryonic cell division?
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G1 and G2.
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What is quiescent state phase?
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G0
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When is DNA synthesized?
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S Phase
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Protein and RNA synthesis occurs in all stages except?
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M Phase
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Cyclins regulated cell cycle. They activate what?
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Cdk (cyclin dependent protein kinases)
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Cyclins are degraded by what?
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ubiquitin-dependent proteolysis
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When do checkpoints occur?
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G1, G2, and M
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