(L14) Cell Cycle, Cancer, and Cell Death Flashcards
What are the molecular regulators of the cell cycle? L14 S15
Cyclins:
-levels increase or decrease during certain times of cell cycle indicating the current phase
Cyclin dependent kinase (CDK):
- kinases that are active when bound to their specific cyclin
- kinase activity regulates relevant enzymes for the current phase of cell cycle
Cyclin dependent kinase inhibitor (CKI):
-inhibit CDKs
How are CDKs regulated?
L14 S18
Requires cyclin binding
Three phosphorylation sites:
- 1 activating (T-loop)
- 2 inactivating
What are the main cyclins?
L14 S17
- A
- B
- D
- E
What are the major inhibitory regulators of the cell cycle?
L14 S22
p21:
-adds inhibitory phosphate to CDKs
p27
p16/INK4
What events trigger entry into cell cycle?
What is the transcripition factor for this and what does it stiumulate?
L14 S23
Mitogen binds receptor which activates Ras by replacing GDP with GTP.
Ras-GTP activates RAF, RAF phosphorylates MEK, MEK phosphorylates MAP, and MAP phosphorylates Myc.
Myc is a transcription factor that:
- stimulate cyclin D transcription
- stimulates p27 degradation
- stimulates E2F transcription
What is the R point in the cell cycle?
L14 S25
Restriction point or G1 checkpoint
It occurs during late G1 and after the cell proceeds through, it is commited to dividing.
What cyclin/CDK complex allows for progression through the R point?
What is the mechanism?
L14 S17;25
Cylcin D-CDK4/6
Hypophosphorylates Rb (retinoblastoma protien) which inhibits E2F
What cyclin/CDK complex allows for progression through the G1 ► S checkpoint?
What is the mechanism?
L14 S17;24
Cylcin E-CDK2
Hyperphosphorylates pRb causing it to release E2F. E2F causes transcription of more cylin E and E2F, amplifying the process.
Initiates assembly of pre-replicaiton complex.
What cyclin/CDK complex allows progression through S phase?
What is the mechanism?
L14 S17;27
Cyclin A-CDK2
Stabilizes replicaiton complex.
What cyclin/CDK complex allows progression from S ► G2?
What does this compelx do?
L14 S17;25
Cyclin A-CDK1
Stimulates production of cyclin B.
What cyclin/CDK complex allows progression from G2 ► M?
What is the mechanism?
L14 S17;28
Cyclin B-CDK1
Activates CDC25 phosphorylase which activates more CDK1.
Initiates mitotic spindle assembly.
What is the function of CDC25?
L14 S19;28;30
Phosphorylase that removes inhibiting phosphates from CDKs.
What are ATM and ATR?
What pathways do they activate?
L14 S29-30;32
Both are kinases that are activated when DNA damge is detected.
p53 pathway:
- ATM/ATR phosphorylates Mdm2 causing it to release p53
- p53 activates p21
- p21 places inhibitory phosphate on CDKs
Chk pathway:
- ATM/ATR phosphorylate Chk, activating it
- Chk phosphorylates CDC25, inactivating it
- without CDC25, inhibitory phosphates are not removed from CDK
Differentiate between the terms tumor, neoplasm, and cancer.
L14 S35
Tumor:
-space occupying lesion
Neoplasm:
-abnormal growth caused by abnormal gene regulation
Cancer:
-malignant neoplasm
What are the stages of carcinogenesis?
L14 S38-42
Initiation:
- irreverisble change in DNA sequence
- activation of oncogene or inactivation of tumor supressor gene
Promotion:
- reversible gene activtion or repression
- cellular selection leads to clonal expansion
- once threshold is reached, cancer occurs
Progression:
- it is now cancer
- continued evolution of cancer for optimal growth
What are oncogenes and what are the 3 types?
L14 S44-46
Genes that stimulate cell division and growth
Only needs one copy with enhanced expression (dominant)
Types:
- cellular proto-oncogenes activated by mutation
- viral genes that behave like proto-oncogenes
- viral captured cellular proto-oncogenes
What are the types of viral oncogens?
L14 S47
Type 1, transducing viruses:
-cellular oncogene carried by retrovirus
Type 2, non-transducing viruses:
-cellular oncogene that is activated by viral insertion
Type 3, non-transducing long latency virus:
-viral protein disrupts normal cell cycle regulation
Type 4:
-viral envolope creates inappropriate signaling
What are the main oncogenes?
L14 S51
- growth factors
- growth factor receptors
- signal transduction molecule (ras, raf, src)
- transcription factors (myc)
- cyclins
- anti-apoptotic factors
What are tumor supressor genes?
L14 S52
Genes that repress cell division and growth
Requires both copies to be inactivated; one copy can be inherited as inactivated
What are the main tumor supressor genes?
L14 S53
- p53
- p14
- p16/INK4A
- Rb
What are the methods of treating cancer?
L14 S59-61
Surgery
Radiation (degrades DNA by directly breaking bond or indirectly by creating ROS from water which then break DNA bonds)
Chemotherapy (alkylating agents, intercalating agents, antimetabolites, mitostatic agents, platinum derivatives)
Immunotherapy
What are the types of cell death?
L14 S65
Apoptosis
Autophagy
Necrosis
Mitotic catastrophe
Senescence
What are the morphologic characteristics, cells involved, inflammatory state, and biochemical features of necrosis?
L14 S67-68
Morphology:
- cell membrane: swollen and ruptured
- cytoplasm: vacuolation and organelle degradation
- nucleus: karyolysis
Cells: can occur in all cells
Inflamation: Yes
Biochemical features:
-failure of homeostatic mechanisms such as ATP producting, ion transport, or pH balance
What are the morphologic characteristics, cells involved, inflammatory state, and biochemical features of apoptosis?
L14 S71-72
Morphology:
- membrane: blebing
- cytoplasm: fragmentation and shrinkage
- nucleus: condensation of chromosomes
Cells: mainly hematopoietic cells and liquid tumors
Inflammation: no
Biochemical features:
-loss of membrane asymmetry (externalized phosphatidylserine)
-mitochondrial caspases (caspases 8, 9, and 3)
What are the morphologic characteristics, cells involved, inflammatory state, and biochemical features of autophagy?
L14 S78
Morphology:
- membrane: blebing
- cytoplasm: autophagic vacuoles
- nucleus: partial condensation
Cells: all
Inflammation: no
Biochemical features:
- increased lysosomal activity
- caspase-independent
What are the morphologic characteristics, cells involved, inflammatory state, and biochemical features of mitotic catastrophe?
L14 S81-82
Morphology:
- cell membrane: no changes
- cytoplasm: enlarged (giant cell formation)
- nucleus: fragmentaiton
Cells: most dividing cells
Inflammation: no
Biochemical features:
-abnormal mitosis leading to delayed cell death
What are the morphologic characteristics, cells involved, inflammatory state, and biochemical features of senesence?
L14 S85-86
Morphology:
- membrane: no change
- cytoplasm: flattening and granulation
- nucleus: heterochromatic
Cell: all
Inflammation: yes
Biochemical features:
-activation of p53 or p16 pathways that lead to permanent senescence through p21 or Rb respectively
