Term
|
Definition
| determines whether the cell should proliferate or enter the quiescent G0 state / A good example of such a cell type is the unfertilized egg. It does not proliferate until after it forms a zygote. The zygote can respond to factors influencing rapid proliferation |
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Term
|
Definition
| At this checkpoint, the cell is assessing whether the conditions and requirements of G1 were met. Has the cell grown sufficiently? Is there no DNA damage? If there is no problem, the cell will enter S phase and begin replication. |
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Term
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Definition
| the cell assesses the origins of replication, ensuring that replication is complete, and that only one copy of the genome is made. DNA damage arising from replication is also repaired. If these conditions are met, the cell exits S phase and enters G2. |
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Term
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Definition
| In G2 phase, the cell must complete everything needed prior to entering mitosis. Has the centrosomes been fully replicated? Has all DNA damaged been repaired? |
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Term
| CIP/KIP family of CDK inhibitors |
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Definition
| p21(CIP1), p27(KIP1) and p57(KIP) |
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Term
|
Definition
p16(INK4a), p15(Ink4b), p18(INK4c) and p19(INK4d) / The
INK4 members only bind to CDK4 or
CDK6, displacing the D-type cyclin
subunit. Without the cyclin, the CDK catalytic subunit has no function. |
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Term
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Definition
| Think of the CDK subunit as the engine of a car. It must be associated with a gas pedal. The break is the CDKI. |
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Term
| mid-G1 checkpoint: Protein roll call |
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Definition
| CDK4 or CDK6 is activated by D-type cyclins, and can be inhibited by either CIP/KIP or INK4 CDKIs. |
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Term
| G1/S checkpoint: Protein roll call |
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Definition
| CDK2 is activated by E-type cyclins, and can be inhibited by CIP/KIP CDKIs. |
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Term
| S Checkpoint: Protein roll call |
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Definition
| CDK2 is activated by A-type cyclins, and can be inhibited by CIP/KIP CDKIs. |
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Term
| G2/M checkpoint: Protein roll call |
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Definition
| CDK1 is activated by B-type cyclins, and can be inhibited by CIP/KIP CDKIs |
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Term
| Regulation for Activating CDKs (5 levels) |
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Definition
| 1. Protein synthesis 2. Assembly 3. Phosphorylation (activates) 4. Association of the CDKI in the CDK complex inhibits the CDK activity 5. protein degradation (ubiquitin-mediated) |
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Term
| CDKactivating kinase (CAK) |
|
Definition
for maximal CDK activity,
a specific threonine residue
on the CDK must become phosphorylated by a CDKactivating kinase (CAK). |
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Term
| Regulation with absence of cyclin partner |
|
Definition
In the absence of a cyclin partner, the T-loop is not accessible to
CAK, and remains unphosphorylated. Upon binding a cyclin, the CDK has low level kinase activity, and a conformational change that exposes the T-loop. Upon CAK phosphorylation of Threonine160, the CDK gains
high level catalytic activity. |
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Term
| Retinoblastoma (Rb) protein |
|
Definition
| Rb negatively regulates growth by binding to and inactivating transcription factors needed for S phase gene expression (transcription factor E2F). Rb is one of most commonly inactivated genes by mutations in human cancers, and is referred to as a tumor suppressor gene. |
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Term
| Describe the state of Rb proteins just as a cell enters G1... |
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Definition
| Rb is hypophosphorylated (active), and negatively regulates proliferation by stopping cells from entering S phase. Again, this is accomplished by Rb binding to, and sequestering E2F transcription factors, thereby preventing S phase specific gene expression. |
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Term
| How is Rb inactivated at the mid-G1 checkpoint? |
|
Definition
| If conditions are met for the cell to enter the cell cycle, for example stimulation by growth factors, D-type cyclin expression is induced and activates the early G1 CDKs, CDK4 and CDK6. CDK4-cyclin D and CDK6-cyclin D complexes will phosphorylate Rb and allow progression to the G1/S checkpoint. |
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Term
| Rb and entering S phase... |
|
Definition
If conditions are met to allow entry into S phase, CDK2-cyclin E will be activated, and further phosphorylate Rb to a hyperphosphorylated and inactive state. The fully inactive hyperphosphorylated Rb releases E2F
transcription factors, allow entry into S phase, and expression of S phase proteins (DNA polymerase,
Thymidine kinase, etc…). |
|
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Term
| What does Rb release when it is phosphorylated and what is the result? |
|
Definition
E2F / E2F transcription factors will also induce expression of more cyclin E and E2F, accelerating the progression through the G1/S checkpoint. Cyclin A is also induced by E2F, allowing activation
of S phase function. As the cell completes mitosis, Rb becomes dephosphorylated, thus re-setting the cell cycle in G1. |
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Term
| What is p27's primary function? |
|
Definition
| helps to maintain CDK2-cyclin E inactive |
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Term
| What takes place as cyclin E levels increase? |
|
Definition
| more CDK2-cyclin E becomes active. Another substrate for CDK2-cyclin E is the CDKI, p27. Phosphorylation of p27 targets p27 for SCF ubiquitin-mediated proteosome degradation. |
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Term
| What is the result of more CDK2 activity as p27 is degraded? |
|
Definition
| This accelerates more CDK2 activity, also propelling entry into S phase. P27 also inhibits early CDK2-cyclin A complexes. Degradation of p27 leads to active CDK2-cyclin A, allowing efficient firing of replication origins in S phase. |
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Term
| G2-M checkpoint? CDKi-cyclin B (in S phase) |
|
Definition
The G2-M phase CDK1-cyclin B complexes are synthesized and assembled in S phase (Figure 9), but
maintained inactive by Wee1 phosphorylation at an inhibitory site
(Tyrosine15, Y15). |
|
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Term
| G2-M checkpoint? CDKi-cyclin B (after S phase) |
|
Definition
Once DNA replication complete, CDK1-cyclin B becomes activated by CAK phosphorylation at an activating phosphorylation site (Threonine161, T161), as well as by dephosphorylation by the phosphatase Cdc25 at the inhibitory site (Y15). The active CDK1-cyclin B complex phosphorylates substrates to begin mitotic events, including chromosome condensation, nuclear breakdown,
microtubule remodeling, kinetochore assembly, and the activation of other important mitotic kinases. |
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Term
|
Definition
| Kleisin and cohesin bind the sister chromatids together until Anaphase. In Anaphase, kleisin is cleaved by Separase. |
|
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Term
|
Definition
| Cleaves kleisin / is maintained inhibited by Securin until Anaphase. |
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Term
|
Definition
As cells enter Anaphase, the Anaphase Promoting Complex (APC/C-Cdc20)
ubiquitinates and targets Securin for proteosome degradation. Without Securin, Separase cleaves Kleisin,
breaking the cohesin complex and enabling sister chromatid separation in Anaphase. |
|
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Term
|
Definition
| In late Anaphase, this is accomplished by another APC complex, APC/C-Cdh1. APC/C-Cdh1 ubiquitinates and targets the mitotic cyclins for proteosome degradation. |
|
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Term
|
Definition
Cdh1 is the mitotic cyclin specificity factor for APC/C, but Cdh1 is maintained in an inactive phosphorylated state by G1 CDK
complexes until anaphase. Cdh1 dephosphorylation (activation) occurs in anaphase by a phosphatase
Cdc14. |
|
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Term
| Cancer mutations: Protooncogenes |
|
Definition
A proto-oncogene normally promotes cell survival or proliferation. / A gain-offunction mutation activates
these proto-oncogenes such that it supplies unregulated growth or survival characteristics. |
|
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Term
| Cancer mutations: Tumor suppressor |
|
Definition
| Suppresses growth or survival characteristics, including pro-apoptotic signals, CDKIs, growth inhibitory signals (TGFβ), and more. Mutations are generally recessive loss-of-function mutations that require inactivation of both alleles. |
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Term
| Cancer mutations: Caretaker genes |
|
Definition
| are similar to tumor suppressors in that the mutations are generally recessive loss of function mutations. They normally function to prevent or repair DNA damage. As a result of the loss-of-function mutations, further mutations can creep into the genome, creating genomic instability and additional mutations. |
|
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Term
| Proto-oncogene or tumor suppressor? Ras-MAPK, TGFBeta, Smad, Fos, Rb, CycD, p16, XP, Bax, Bcl-2 |
|
Definition
| PO, TS, TS, PO, TS, PO, TS, TS, TS, PO |
|
|
Term
|
Definition
The earliest mutation is a loss-of-function mutation in the tumor
suppressor gene, APC (Adenomatous polyposis coli). This leads
to initial growth and the development of a benign precancerous cell type. |
|
|
Term
|
Definition
| Another mutation is a gain-of function in a Ras isoform, K-Ras. |
|
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Term
|
Definition
| A third mutation is a loss-of-function mutation in DCC (deleted in colorectal cancer). |
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Term
|
Definition
A loss-of-function mutation often occurs in the tumor suppressor p53. Mutations in p53, or within the p53 pathway are very common in cancers. p53 loss of function allows many benign cancers to progress towards
malignant carcinomas, and more mutations may allow metastasis. |
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Term
| Loss of function: Dominant or recessive? |
|
Definition
|
|
Term
| hereditary (familial) vs. sporadic tumor formation |
|
Definition
| Hereditary require one spontaneous mutation sporadic two --- just remember the obvious |
|
|
Term
|
Definition
The active p53 transcription factor exists as a homotetramer (Figure 9). Each monomer has three domains to its structure. One domain involves the
tetramerization of the monomers. A second domain mediates DNA binding to p53 responsive DNA promoter elements. A third domain involves interactions with other proteins to mediate transcription. |
|
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Term
|
Definition
| A mutation in the tetramerization domain would prevent the mutant from incorporating into a homotetramer with other mutants or wild type monomers. This mutation would be considered a recessive mutation and require LOH to mediate loss-of-function. |
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|
Term
| p53: mutation to the DNA binding region |
|
Definition
| A mutant in the DNA-binding domain (shown with a blue dot) can still form into homotetramers with other mutant and wild type proteins. However, without all four monomer functioning together, the efficiency of DNA binding is severely decreased. Even a single mutant in four can inactivate the complex, essentially creating loss-of-function. Since it is very likely that the complex will contain at least one mutant monomer, this basically creates a LOH situation. As such, these mutations would be considered dominant. |
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Term
| What kind of mutation is responsible for protooncogene Her2? |
|
Definition
| Aberrant dimerization / a point mutation from Val to Glu / ligand-independent active receptors |
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Term
| What kind of mutation is responsible for protooncogene ErbB? |
|
Definition
| Aberrant dimerization / deletion to the extracellular domain / ligand-independent active receptors |
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Term
| What kind of mutation is responsible for protooncogene BCR-Abl? |
|
Definition
| Translocation between chromosomes 9 and 22 results in der(9) and Philadelphia chromosomes. The Philadelphia chromosome contains a gene fusion to generates the BCR-Abl fusion protein. BCR-Abl is a constitutively active kinase that inappropriately phosphorylates substrate altering their functions inside the cell, causing chronic myelogenous leukemia. |
|
|
Term
| What kind of mutation is responsible for Burkitts lymphoma? |
|
Definition
| A translocation between chromosome 8 and 14 causes the over-expression of the c-Myc transcription factor in B cells |
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|
Term
| What happens in response to DNA damage (ATM related)? |
|
Definition
In response to DNA damage, ATM (or ATR) mediates the inactivation of CDK complexes by inhibiting Cdc25 phosphatase function. ATM phosphorylates and activates Chk1/2.
Chk1/2 then phosphorylates Cdc25, leading to ubiquitin-mediated degradation. As a result, the inhibitory phosphorylation
(Tyrosine15) on the CDK catalytic subunit remains and the CDK complex is inactive. |
|
|
Term
|
Definition
In addition, ATM/ATR mediates CDKI
expression (p21) through the transcription factor p53 (2). ATM phosphorylates p53, stabilizing this transcription factor. Combined, this all causes cell cycle arrest. |
|
|
Term
|
Definition
Mdm2 in the unphosphorylated state
promotes the degradation of p53. As a result of Mdm2 phosphorylation, p53 is more stable. |
|
|
Term
|
Definition
| Another transcriptional target for p53 is Arf14. Arf14 can bind to Mdm2 an sequester it in the nucleolus, thereby preventing Mdm2 from destabilizing p53. |
|
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Term
|
Definition
Arf14 and p16 have separate first exons, but through an alternative
splicing mechanism, they share exon 2 coding sequence in alternate reading frames / a deletion in exon 2 would inactivate both ARF and p16. As a result, both the p53 and the Rb
tumor suppressor pathways would be affected by a single mutation. |
|
|
Term
| Endocrine Therapy in premenopausal Patients |
|
Definition
Premenopausal ovaries make
large quantities of estrogen which the cancer uses to stimulate growth... use tamoxifen! |
|
|
Term
| Endocrine Therapy in Postmenopausal Patients |
|
Definition
Had she been postmenopausal, the estrogen levels are greatly reduced, and the manner in which the estrogen is produced is different. In postmenopausal women, the adrenal gland produces circulating androgens. Aromatase, produced from fat cells, converts the androgens to estrogens. This provides an alternative treatment for postmenopausal
women, the use of Aromatase Inhibitors (AI) |
|
|
Term
| Aromatase Inhibitors (AI) |
|
Definition
| AIs inhibit the production of low levels of estrogens, thereby depleting the ER of its ligand. This also removes the potential negative side effects from Tamoxifen use. |
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Term
| What is the first step, the causing factor, that induces angiogenesis in a tumor? |
|
Definition
| Hypoxia releases growth factors (GFs, FGF,TGFα, VEGF) from the tumor and surrounding cells. |
|
|
Term
| Tumor angiogenesis: What will the release of growth factors do to the tumor? |
|
Definition
| Vascular endothelial cell (EC) receptors [RTKs] binds to the GFs and shift the EC from a G0 quiescent state into the active cell cycle (proliferation). This stimulates EC growth and migration towards the tumor. |
|
|
Term
| Tumor angiogenesis: Last step involving ECM... |
|
Definition
| Extracellular matrix (ECM) communication involving Integrins promotes the remodeling of extracellular matrix by matrix metalloproteinases (MMPs), enabling movement of cells through the ECM to create a new vascular tube. |
|
|
Term
|
Definition
| Drug: Inhibits VEGF. Thus disrupts the creation of tumor vascular growth |
|
|
Term
|
Definition
| Drug: Inhibits MMP. Thus, makes new tumor vascular structures unable to wind through ECM. |
|
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Term
| Metastasis and angiogenesis |
|
Definition
| The new blood vessels produced during angiogenesis lack a more permanent basement membrane. The cells are also composed of both endothelial and tumor cells. As a result, the vessels are “leaky”. Tumor cells can easily penetrate the defective vessels and disseminate (metastasize) to new locations through the circulation. |
|
|
Term
| The benign to metastatic shift |
|
Definition
1. there is a loss of cell to cell adhesion, involving E-cadherin. MMPs digest this ECM and tumor capsule and allow movement of tumor cells outside
their original location. 2! Considering these same features
are seen in angiogenesis, it is not
surprising that metastasis is also
induced by hypoxia, and involves
the activation of extracellular
MMPs. |
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