Cell Cycle, Apoptosis, And Cancer Flashcards
What happens in S phase
DNA synthesis/replication
Histone syntheisis
Centrosome formed
Chromosome duplication
What happens in M Phase
Mitosis (PMAT)
- chromosome duplication/segregation
- cytokinesis
What happens in G1 phase of interphase ?
RNA and protein synthesis needed for DNA replication
*no cell division
What happens in G2 phase of interphase ?
DNA stability is checked
*prep for mitosis
What happens in G0 stage of the cell cycle?
Nothing. No division occurs.
What drives cell proliferation in cell signaling networks
Myc-TF
Myc is a gene regulatory protein
Myc increases _________ levels in the cell to drive proliferation
G1-Cyclin-dependent kinase (CDK) levels
CDK phosphorylates what in cell cycle that drives cell proliferation
Retinoblastoma (Rb)
Phospho-Rb (created from CDK) releases what in cell signaling that drives cell proliferation
Releases sequestered E2F (elongation factor)
*phophorylated RB is “inactive”. It releases the E2F protein to go on in its active form
Binding of Cyclin to CDK only causes partial activation of CDK. What is needed for full activation of CDK?
CDK-activating kinase (CAK)
*adds phosphate to T-loop “cave site”
What are the CDK inhibitors (CKI) that inhibit cyclin-CDK complex?
WEE1
- phosphorylate CDK complex inactive by added phosphate to the “roof site”
P27 (KIP1)
-bind to attached CDK complex (both the cyclin and CDK) and make it inactive
What opposes WEE1 inhibition of the CDK complex ?
CDC25 phosphatase
- removes the phosphate attached by WEE1 kinase to make it active again
- dephosphorylates the “roof site”
APC/C is activated by binding to _____
CDC20
*starts ubiquitination pathway
The Activated APC/C poly-ubiquitinates it substrates. What are two proteins ubiquitnated by APC/C in the cell cycle? And why does this proteins need to be down regulated?
S- and M- cyclin proteins
**cyclin-S and cyclin-M activity must be inhibited to move the cell into anaphase. Without the cyclins the CDK is inactivated.
**both S- and M- proteins are sent to proteasome to get degraded
What E3 ubiquitin ligase keeps P53 inactive though degradation in quiescent cells ?
MDM2
DNA damage (increases or decreases) protein kinase activity?
Increases
*protein kinase phosphorylates P53 to make it active
Activation of P53 leads to (increased or decreased) transcription of specific CKI (P21).
What is the effect on the cell cycle?
Increased
*binding and inactivation of cyclin-CDK by P21 causes cell cycle arrest
What hyperphosphorylates RB to make it inactive to release active E2F?
CyclinD-CDK 4 and 6 complex’s
*which helps the cells pass though the restriction point in G1
Briefly describe the extrinsic pathway of cell apoptosis.
*mitochondrial-independent pathway
- A Fas ligand and TNFa binds to Fas receptor and TNFa receptor on the outside of the cell
- FADD complex will activate production of Procaspase-8
- TRADD complex will stimulate activiation of procaspase-8 to caspase-8
- Caspase-8 will activate procaspase 3,6,7 to caspase 3,6,7.
- Active caspase 3,6,7 will initiate apoptosis
Briefly describe the intrinsic pathway of apoptosis.
*mitochondrial dependent because relied on cytochrome C
- DNA damage activates P53
- Active Caspase 8 will convert Bid to tBid and activate BAX and BAK
- P53, BAX, BAK stimulate release of cytochrome C from the mitochondria
- APAf-1 adds cytochrome C to an apoptosome
- The Apoptosome activate procaspase 9 to caspase 9
- Caspase 9 activates procaspase 3, 6, 7 to caspase 3, 6,7
- Caspase 3, 6,7 signal apoptosis
**BCL-2 inhibits release of cytochrome C from mitochondria and the function of APAF-1
What are the key regulators of the intrinsic pathway of cell apoptosis ? And what do they do ?
BAX and BCL-2
BAX
- stimulates release of Cyt C from the mitochondria and therefore stimulate the intrinsic apoptosis pathway
BLC-2
- inhibits the release of Cyt C from the mitochondria
- inhibits APAF-1 function of adding cyt C to apoptosome
- therefore inhibits the intrinsic pathway of apoptosis
What are the two major classes of caspases ?
- Initiators
- caspase 8 and 9
- activate many other caspases - Executioners
- caspase 3
- destroys the target by apoptosis
Apaf1 (in the intrinsic apoptosis pathway) is activated by what? What results in what?
- Activated by the cytochrome C and hydrolysis of ATP
- creates the CARD domain which helps assemble the apoptosome (cyt c/apaf1 complex) by the exchange of ADP for ATP
- CARD domain and the apoptosome help activate procaspase 9
- caspase 9 activates executioner procaspases
HER2 receptor is a common proto-oncogene in the body. What is the oncogene associated with this RTK Proto-oncogene? And what is the disease associated with the mutation?
HER2 receptor (RTK)
-point mutation changes valine to glutamine
*becomes NEU
-dimerizes RTK and tyrosine kinase activity turned on without ligand.
=BREAST CANCER
EGF receptor is a common proto-oncogene in the body. What is the oncogene associated with this RTK Proto-oncogene? And what disease is associated with this mutation?
EGF receptor (RTK) -deletion occurs *EGFRvIII is created -receptor tyrosine kinase activity is constantly active = GLIOBLASTOMA
Chromosome 9 and 22 are common proto-oncogenes in the body. Translocation of these acrocentric genes causes formation of what oncogenes? What is the disease associated with this mutation?
Chr 9 (with ABL gene) and Chr 22 (with BCR gene)
- translocation occurs
- der(9) and der(22) is created
- both BCR and ABL gene are now on der(22)
*expression of der(22) causes BCR-ABL fusion protein which causes CHRONIC MYELOGENOUS LEUKEMIA (CML)
Point mutation of the RAS proto-oncogene changes what two amino acids and results in a RAS oncogene that is perpetually active and cause 25% of all cancers
Changes glycine to valine
Gene amplification of N-MYC proto-oncogene results in what oncogene function? And causes what type of cancer?
Results in elevated levels of N-MYC transcription factor
-seen in Neuroblastoma
A chromosomal translocation in the proto-oncogene c-MYC (between chr 8 and 14) results in what? And causes what type of cancer?
Causes MYC transcription factor to be over expressed
-seen in Burkitt Lymphoma
Mutation or deletion of one copy of RB1 (gene that encodes Rb) predisposes the cell to be cancerous. The heterozygous RB1 is passed on to the child. A second “hit” by somatic mutation causes the cell to become cancerous and form tumors in highly proliferative tissues. This is what form of retinoblastoma cancer?
Hereditary form of Rb
- causes cancer in both eyes and proliferative tissues
- Rb is a tumor suppressor so mutation causes constant transition from G1 to S which causes cancer
Retinoblastoma is a proto-oncogene. In some forms of Rb cancer, both copies of the RB1 genes are mutated by two independent mutations. This is what form of Rb cancer?
Sporadic form of Rb,
Non-hereditary and non-cancerous cells are fine. Therefore can have the cancer in just one eye.
*hereditary have it in both eyes
Decreased DNA repair inactivates tumor suppressor function and promotes activation of oncogenes. Therefore ______ function to promote DNA repair proteins
Tumor suppressors
What tumor suppressor has a mutation related to 70% of prostate cancer?
PTEN-Phosphatase and tensin homolog
What tumor suppressor has a mutation associated with colon cancer ?
APC- Adenomatous polyposis Coli
*chr 5 mutation
What chromosome is associated with the tumor suppressors P53, BRCA, and NF-1 gene and has a mutation that is associated with more than 50% of all human tumors, breast cancer, and neurofibromatosis ?
Chromosome 17
What is the normal function of the tumor suppressor NF-1 gene?
- encodes a GTP-ase activating protein (GAP) which turns off activated RAS protein
- neurofibromatosis
What chromosome is associated with the tumor suppressor RB gene?
Chromosome 13
*mutuation seen in retinoblastoma
What chromosome is associated with the tumor suppressor APC and a mutation that causes colon cancer ?
Chromosome 5
Hallmark traits of both benign and malignant tumors
- Self sufficiency in growth signals
- Evading growth suppressors (stop growth inhibition and promote growth )
- Enabling replicative immortality (enabling telomerase activity which prevents telomere shortening and death of cell)
- Inducible angiogenesis ( develop new blood vessels)
- Resist cell death (defect intrinsic and extrinsic apoptosis pathways)
- Deregulate cellular energetics (have high rates of glycolysis by upregulating GLUT1)
- Avoiding immune destruction (invisible to T and B lymphocytes)
- Tumor-promoting inflammation (reactive oxygen may accelerate mutagenesis of cancer cells)
- Genome instability and mutation (promote further mutation by epigenetics)
Integrated HPV affects E6 and E7 which causes degradation/effects of what tumor suppressors?
E6
-causes P53 degradation -increased telomerase expression
E7
- unbindss E2F from Rb (and keeps Rb bound to it) which allows proliferation of DNA
- inhibits P21 which increases CyclinD-CDK4 activity (which also promotes E2F to move through and synthesize DNA
EBV is a DNA virus implicated in what type of cancer
- Burkitt lymphoma
- Nasopharyngeal carcinoma
Kapoi sarcoma associated herpesvirus (KSHV) is an RNA virus implicated in what type of cancer
Kapoi sarcoma
*seen in those infected with HIV
What are some types of chemotherapeutic agents
- alkylating agents
- antimetabolites
- topoisomerases 1/2 Inhibitors
- cytotoxic antibiotics
- mitosis inhibitors
In targeted inhibition of oncoproteins, what inhibits the HER2 receptor and the mutated NEU receptor?
Herceptin
Trastuzumab
In targeted inhibition of oncoproteins, what inhibits the EGF receptor (and consequently the ERBB mutated receptor)?
Erbitux
Cetuximab
In targeted inhibition of oncoproteins, what inhibits the formation of the BCR-ABL fusion protein?
Gleevec
Imatinib mesylate
Herceptin (the HER2 inhibitor) has what mechanism of action?
- The antigen binding region of trastuzumab blocks cleavage and dimerization of HER2 (which blocks phosphorylation of second messenger)
- The humanized region of it bings to the immune effector cell which activates the anti-body dependent cell-mediated cytotoxicity
- Leads to tumor-cell lysis
- Leads to HER2 degradation
*INHIBITS HER2 CLEAVAGE AND DIMERIZATION
What is the mechanism of action for gleevec inhibition of BCR-ABL fusion protein formation?
ATP is normally needed for the BCR-ABL enzyme to phosphorylate the target protein and cause CML
- gleevec inhibits the binding of ATP to the BCR-ABL fusion protein therefore stopping the phosphorylation of the target protein and stopping CML
- INHIBITS ATP BINDING OF THE ENZYME
What is the mechanism of action for the cetuximab inhibition of EGF receptor?
Erbitux inhibits the ligand binding to the EGF receptor. The tyrosine kinase is not phosphorylated and there is no activiation of the signal transduction pathway.
*INHIBITS LIGAND BINDING TO RECEPTOR
Which strand of HPV causes cervical cancer and manifestations in the mouth ?
16 and 18
