Term
| Where will DNA binding domains of nuclear receptors bind? |
|
Definition
|
|
Term
| What are the two kinds of DNA consensus elements? |
|
Definition
| Inverted repeats and direct repeats |
|
|
Term
| Describe inverted repeats and the type of receptors they bind? |
|
Definition
| Type I nuclear receptors bind to steroid based hormones (estrogens, androgens, glucocorticoids, mineralocorticoids), and use the inverted DNA consensus sequences. |
|
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Term
| Describe direct repeats and the type of receptors they bind? |
|
Definition
Type II nuclear receptors
bind to other lipophilic hormones (Vitamin D, Retinoic Acid, Thyroxine)
and use the direct repeat DNA consensus sequences. |
|
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Term
| Where is the type I nuclear receptor pre-ligand binding and what is it doing? |
|
Definition
In the absence of the hormone ligand, Type I nuclear receptors exist in the cytoplasm in an inactive state
bound to inhibitors The inhibitor blocks the ligandbinding domain (LBD), and in this form the receptor
may be in a conformation that obscures the DNAbinding
domain (DBD). |
|
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Term
| What is usually the inhibitor of a type I nuclear receptor? |
|
Definition
|
|
Term
| What happens in a type I nuclear receptor once the ligand has bound? |
|
Definition
| 1. The inhibitor displaces the inhibitor and induces a conformational change in the receptor that exposes the DBD. 2. The active receptor:ligand complex migrates to the nucleus, and forms homodimers that bind inverted repeat consensus DNA elements in target genes. |
|
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Term
| What happens once the type I active receptor:ligand complex migrates to the nucleus? |
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Definition
| The homodimer complex also recruits transcriptional coactivators and chromatin remodeling complexes (SWI/SNF, HATs) to unwind the DNA into a more transcriptionally active euchromatin structure. |
|
|
Term
| Where are type II nuclear receptors located? What is it bound to? |
|
Definition
| In the nucleus / RXR at direct DNA repeat sequences |
|
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Term
| Type II nuclear receptors not bound to ligand? |
|
Definition
In the absence of a hormone ligand, the type II nuclear receptor complex is bound with transcriptional
corepressors (HDAC) that mediate heterochromatin DNA structure and suppress gene expression. |
|
|
Term
| Type II nuclear receptor once it IS bound to a ligand? |
|
Definition
The hormone ligand is lipophilic,
capable of traversing the plasma and nuclear membranes. Upon ligand binding to the type II receptor complex, the corepressors are displaced and transcriptional coactivators and chromatin remodeling complexes (SWI/SNF, HATs) are recruited. This mediates changes in transcription and gene expression. |
|
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Term
|
Definition
| Many breast cancers (BC) require estrogen signaling to maintain cancer growth. These ER (+) cancers can be effectively treated with Tamoxifen (brown shape), an estrogen analog. |
|
|
Term
|
Definition
| Tamoxifen is not a drug of choice in ER (-) BC. |
|
|
Term
| Selective Estrogen Receptor Modulators (or SERM), UEC, and Tamoxifen |
|
Definition
Unfortunately, what works in ER (+) BC does not work in ER (+) uterine
endometrial cancer (UEC). In fact, Tamoxifen activates ER-responsive transcription just fine, stimulating endometrial cell proliferation. As a result, Tamoxifen, used to treat ER (+) BC increases the risk of the patient developing UEC. Since the patient has BC, but not UEC, one must weigh the pros and cons of treating the patient with Tamoxifen. Tamoxifen can effectively treat ER (+) BC, but it also strengthens bones, and
lowers LDL cholesterol. However, Tamoxifen also can increase the risk of UEC and developing blood clots. |
|
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Term
| Prostate Cancer: What do serum androgen activate in prostate stromal and epithelial cells? |
|
Definition
| Type I androgen receptors |
|
|
Term
| Prostate Cancer: What will activated androgen receptor secrete? |
|
Definition
| Growth factors (GF) and survival factors (SF) |
|
|
Term
| Prostate Cancer: What will GF and SF bind to and activate? |
|
Definition
| These factors bind to RTK receptors in the prostate endothelial cells and promote growth. The activated AR in the stromal cells mediates secretion of prostate serum antigen (PSA). |
|
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Term
|
Definition
| LHRH agonists / While as a LHRH agonist there is an initial increase (or flare) of testosterone production, this flare disrupts the normal feedback regulation of LHRH and LH for the production of testosterone. As a result, the levels of testosterone will drop 90 to 95 percent to what is called castrate level. |
|
|
Term
Mechanisms of Hormone Refractive Cancer: Cross-talk between signaling
pathways. |
|
Definition
In addition to normal nuclear receptor
signaling, the nuclear receptors
can also become activated by other pathways, even involving G protein coupled receptors or Receptor tyrosine kinases. This can cause ligandindependent AR activation. |
|
|
Term
Mechanisms of Hormone Refractive Cancer: Selective activation of an
alternative oncogenic pathway |
|
Definition
| Mutations in an alternate pathway can provides the cellular effects that the ablation therapy eliminated. For example, if survival and growth factors were eliminated by the ablation therapy, perhaps a mutation in Her2 could hyperstimulate these survival and/or growth factors. The factors need not come from AR signaling. As long as they are provided, that is all that counts. |
|
|
Term
Mechanisms of Hormone Refractive Cancer: Mutation
in the AR |
|
Definition
Under normal conditions, androgens such as testosterone (purple pentagon)
can bind to the AR and stimulate its signaling. Flutamide is the antagonist of testosterone used to
prevent AR signaling. However, perhaps a mutation alters the binding site, such that when flutamide binds, it now provides the structural basis for efficient AR signaling. Perhaps a
mutation can allow other low affinity agonists to bind and stimulate AR signaling. Finally, perhaps the mutation allows the low affinity agonist to bind with high affinity. In each case, the adrogen ablation therapy would be ineffective. |
|
|
Term
| Mechanisms of Hormone Refractive Cancer: The receptor could become overexpressed... |
|
Definition
| or the coactivators (Steroid Receptor Coactivator, SRC) and/or cosuppressors (Nuclear Receptor Corepressor, NCoR) could become altered in their expression levels |
|
|
Term
| Give me some info on Wnt? |
|
Definition
| Contains a palmitate modification that ties the ligand to the membrane / Binds to frizzled |
|
|
Term
|
Definition
| Armadillo, contains seven transmembrane-spanning domains |
|
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Term
| Description of system (frizzled / Wnt) without a ligand attached... |
|
Definition
| a transcription factor, -Catenin is phosphorylated in the cytosol bound in a multiprotein complex with Axin, Adenomatosis Polyposis Coli (APC), and Glycogen Synthase Kinase-3 (GSK-3). Phosphorylation targets - catenin for ubiquitin-mediated degradation. Inside the nucleus is another transcription factor, TCF. In the absence of -Catenin, TCF acts as a transcriptional repressor to inhibit transcription of target genes. |
|
|
Term
|
Definition
| TCF in nucleus acts as a transcriptional repressor to inhibit transcription of target genes. |
|
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Term
| Description of system (frizzled / Wnt) with a ligand attached... |
|
Definition
Fz phosphorylates a coreceptor,
LRP. Phospho-LRP has a high affinity for Axin. As a result, this disrupts the Axin/GSK-3/-catenin cytosolic complex, and -catenin does not become
phosphorylated, ubiquitinated or degraded. |
|
|
Term
| Unphosphorylated beta catenin |
|
Definition
-catenin can translocate into
the nucleus, binds to TCF, and acts as transcriptional activator of target genes |
|
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Term
| Post transcriptional modification of hedgehog |
|
Definition
| The Hh ligand is synthesized as precursor, which undergoes autocleavage and modifications, attaching the cleavage product to cholesterol and palmitate. |
|
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Term
| Where will you find modified hedgehog? |
|
Definition
These modifications occur intracellular, but when it is
secreted, the ligand becomes tethered by these modifications to the plasma membrane. |
|
|
Term
| What affect does the sequestering of hedgehog have in the cell? |
|
Definition
| This limits the range of action of the Hh ligand, and produces morphogenic effects, temporal and spatial Hh concentration gradient, which affects cells differently and alters their cell fates. |
|
|
Term
|
Definition
| is a seven transmembrane-spanning protein that is related to the Wnt Fz receptor. The Hh receptor Patched (Ptc) contains twelve transmembrane-spanning domains. |
|
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Term
| In absence of Hh ligand: Description of system (Hedgehog) without a ligand attached... |
|
Definition
Ptc is located in the plasma
membrane, and mediates Smo internalized in a vesicle membrane. Fu, Cos2, CI are all bound together. |
|
|
Term
| In absence of Hh ligand: Post Ci phosphorylation |
|
Definition
Ci phosphorylation causes its partial Ub-mediated degradation to a
smaller Ci75 product. Ci75 translocates to the nucleus and represses transcription. As a result of no Hh ligand, the Ptc protein represses
target genes by inhibiting signaling of full length Ci. |
|
|
Term
| In presence of the Hh ligand: What happens to Pct? |
|
Definition
| Hh binds Ptc. Ptc becomes inhibited and is also internalized in a vesicle membrane. |
|
|
Term
| In presence of the Hh ligand: What happens to Smo? |
|
Definition
| As such, Smo is not internalized and moves to the plasma membrane, and becomes phosphorylated. |
|
|
Term
| In presence of the Hh ligand: What happens to phosphorylated Smo. What does it do? |
|
Definition
This affects the binding of the
cytosolic complex. With the dissociation of the Fu/Cos2/Ci complex,
Cos2 binds Smo, and both Cos2/Fu become phosphorylated. This leaves Ci free in cytoplasm in an unbound and full length form. |
|
|
Term
| In presence of the Hh ligand: What happens once Ci is free in the cytoplasm? |
|
Definition
Ci is no longer microtubule-bound, translocates to nucleus, and binds cAMP responsive elements (CRE) in DNA with CBP (CRE Binding Protein) to mediate
target gene transcription. |
|
|
Term
|
Definition
involves the phosphorylation and
ubiquitin-mediated proteolysis of a TF inhibitor protein, I-B, in a rapid response to stress signals. |
|
|
Term
| Examples of stress factors that activate NF-KB... |
|
Definition
Such signal can include infection (viral, bacterial, fungal), ionizing
radiation, ligand binding to the Tumor Necrosis Factor-α (TNF-α), ligand binding to the Interleukin-1 (IL-1)
receptor. |
|
|
Term
| NF-KB pathway: Activated, physphorylated I-KB kinase |
|
Definition
Activated I-B kinase causes the phosphorylation and
ubiquitin-mediated proteolysis of I-Bα. |
|
|
Term
| NF-KB signaling: The degradation of I-KBalpha does what? |
|
Definition
The degradation of I-Bα liberates/activates the stress responsive TF, NF-B. NF-B translocates to the nucleus and induces expression of cellular processes that respond to the stress. In addition, NF-B also promotes the expression of more
I-Bα, as a negative feedback to the signal pathway. |
|
|
Term
| What is Notch Signaling used for? |
|
Definition
The Notch signaling pathway is one mechanism by which
two neighboring cells can communicate. The pathway derives its name from the receptor. |
|
|
Term
| What is the ligand in Notch Signaling, and where do you find it? |
|
Definition
The Notch receptor binds its ligand (Delta or Serrate), which is located in the plasma membrane of an adjacent cell. Notch possess a
Delta-binding domain, while Delta possess a Notch-binding domain |
|
|
Term
| Notch Signaling: What happens immediately post ligation of molecules? |
|
Definition
Ligation between the two molecules causes Notch to undergo two cleavage events, referred to as Regulated
Intramembrane Proteolysis (RIP). |
|
|
Term
| Notch Signaling: The first cleavage. |
|
Definition
| The first cleavage is in the extracellular matrix, and the enzyme that cleaves Notch in its extracellular domain is referred to as a Matrix MetalloProtease (MMP, ADAM10). |
|
|
Term
| Notch Signaling: The second cleavage. |
|
Definition
The second cleavage is intracellular, and the enzyme that cleaves Notch
(presenilin-1, PS-1) is referred to as a -Secretase. The second cleavage
releases a Notch cytosolic domain, which acts as a TF in the nucleus. This mediates change in development/cell
fate in the responding cell. |
|
|
Term
| Phospholipase C can be activated by G proteins. What else can activate it? |
|
Definition
| RTKs and cytokines can also activate PLC. |
|
|
Term
| What kind of receptors produce PI-3 and how is it done? |
|
Definition
| RTKs and cytokine receptors / phosphorylation of carbon 3 |
|
|
Term
| Function and structure of PI-3 |
|
Definition
PI-3 kinase consists of catalytic and SH2-containing subunits. The SH2
domain binds phosphotyrosine residues on the active receptors, which
again positions the enzyme near its substrates: PI 4-phosphate or PI 4,5-
bisphosphate |
|
|
Term
| What will PI 4,5-bisphosphate and PI 3,4,5 triphosphate accomplish? |
|
Definition
| These PI-3 phosphate derivatives further transduce the signal by activating the Protein Kinase B (PKB, also referred to as AKT) signaling pathway. The PKB/AKT pathway promotes cell division and/or survival (anti-apoptotic) signals. |
|
|
Term
| What do PI-3 derivative activate PKB |
|
Definition
| Upon exposure to PI-3 derivatives, a PH domain on PKB binds to the PI-3 derivatives. |
|
|
Term
| What are the results of PI-3 derivative / PKB binding? |
|
Definition
| First, PKB becomes localized to the membrane. Second, there is a conformational change in the kinase, causing a release of inhibition on the catalytic domain. This partially activates PKB. The kinase becomes fully activated by further phosphorylation by two additional kinases (PDK1 and PDK2). |
|
|
Term
| What kind of kinase is PKB? |
|
Definition
| The fully active PKB is a Ser/Thr kinase. |
|
|
Term
| What happens once PKB is fully activated? |
|
Definition
| Once activated, PKB dissociates from the plasma membrane into the cytosol. PKB promotes cell survival characteristics. |
|
|
Term
| What the PKB related mechanisms that promote cell survival? |
|
Definition
| First, PKB phosphorylates and inactivates many pro-apoptotic proteins. Second it phosphorylates and sequesters many TFs (Forkhead) in the cytosol, which would mediate transcription of pro-apoptotic proteins. |
|
|
Term
|
Definition
| PKB also promotes glucose uptake and storage. The Insulin receptor (a RTK) can activate PKB, and mediate movement of Glucose transporter molecules(GLUT4) from intracellular vesicles to the plasma membrane. This increases glucose uptake, primarily into muscle and fat cells, and lowers blood glucose concentrations. |
|
|
Term
|
Definition
In the liver and muscle, insulin activates PKB, which phosphorylates and inactivates Glycogen Synthase Kinase 3
(GSK3). This maintains GSK3 in its active form, so that glycogen synthesis occurs. |
|
|
Term
| What de phosphorylates PKB? Where will you find plenty of XXXX problems? |
|
Definition
|
|
Term
| SREBP(Sterol Regulatory Element Binding Protein) |
|
Definition
| TF that will activate transcription of cholesterol biosynthesis genes |
|
|
Term
| SCAP (SREBP Cleavage Activating Protein) |
|
Definition
Promote proteases to cleave SREBP into
an active nuclear TF. |
|
|
Term
|
Definition
|
|
Term
| In the case where there is sufficient cholesterol for the needs of the cell... SREBP/SCAP/Insig-1(2) |
|
Definition
| Insig-1(2) binds the sterol sensing domain of SCAP, anchoring SCAP and SREBP in the ER. SREBP remains as an intact and inactive TF. |
|
|
Term
| In the case where there is insufficient cholesterol for the needs of the cell... SREBP/SCAP/Insig-1(2) |
|
Definition
| there is a dissociation of insig-1(2) to SCAP and SREBP. Both SCAP and SREBP are transported to the Golgi, where SREBP is cleaved. A cytosolic fragment, nSREBP, is the activated TF that is transported to the nucleus, and thereby mediates transcription of cholesterol biosynthesis genes and LDL receptor. |
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