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36 Cards in this Set

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What is a kinase?
This is an emzyme that phosphorylates things, other things, itself.
What are the basic functions of B-Catenin?
β-Catenin has important roles in cell–cell adhesion and in the regulation of gene transcription. Mutations that stabilize β-catenin are common in cancer, but it remains unclear how these mutations contribute to cancer progression. β-Catenin is also a centrosomal component involved in centrosome separation.
What is aneuploidy?
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders (birth defects). Some cancer cells also have abnormal numbers of chromosomes.[1] Aneuploidy occurs during cell division when the chromosomes do not separate properly between the two cells.
What is haploinsufficiency?
Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy of the gene does not produce enough of a gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state. It is responsible for some but not all autosomal dominant disorders.

Haploinsufficiency is therefore an example of incomplete or partial dominance, as a heterozygote (with one mutant and one normal allele) displays a phenotypic effect.

Haploinsufficiency can occur through a number of ways. A mutation in the gene may have erased the production message. One of the two copies of the gene may be missing due to a deletion. The message or protein produced by the cell may be unstable or degraded by the cell.
What is cyclin D and why is it important in bladder cancer?
mplification of 11q13 involving cyclin D1 gene (CCND1) is among the most common sites of gene amplification in T1-T2 high grade tumors [4-6]. Cyclin D1 plays an important role in cell cycle, binds to cyclin dependent kinases (CDK4/6), and promotes phosphorylation of RB1, orchestrating progression through the G1 restriction point.
What is a centrosome?
Centrosomes are composed of two orthogonally arranged centrioles surrounded by an amorphous mass of protein termed the pericentriolar material (PCM). The PCM contains proteins responsible for microtubule nucleation and anchoring[7] including γ-tubulin, pericentrin and ninein. In general, each centriole of the centrosome is based on a nine triplet microtubule assembled in a cartwheel structure, and contains centrin, cenexin and tektin.
What is FISH?
FISH (fluorescence in situ hybridization) is a cytogenetic technique developed by Christoph Lengauer that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high degree of sequence similarity. Fluorescence microscopy can be used to find out where the fluorescent probe bound to the chromosomes [1]. FISH is often used for finding specific features in DNA for use in genetic counselling, medicine, and species identification. FISH can also be used to detect and localize specific mRNAs within tissue samples. In this context, it can help define the spatial-temporal patterns of gene expression within cells and tissues.
What is a prokaryote?
*This is an organism that doesn't have a cell nucleus. Pro - meaning before and karyon - meaning nucleus.
What is alternative splicing?
Alternative splicing (or differential splicing) is a process by which the exons of the RNA produced by transcription of a gene (a primary gene transcript or pre-mRNA) are reconnected in multiple ways during RNA splicing. The resulting different mRNAs may be translated into different protein isoforms; thus, a single gene may code for multiple proteins.[1]

Alternative splicing occurs as a normal phenomenon in eukaryotes, where it greatly increases the diversity of proteins that can be encoded by the genome;[1] in humans, ~95% of multiexonic genes are alternatively spliced.[2] There are numerous modes of alternative splicing observed, of which the most common is exon skipping. In this mode, a particular exon may be included in mRNAs under some conditions or in particular tissues, and omitted from the mRNA in others
What is a fusion protein?
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins. Recombinant fusion proteins are created artificially by recombinant DNA technology for use in biological research or therapeutics. Chimeric mutant proteins occur naturally when a complex mutation, such as a chromosomal translocation, tandem duplication, or retrotransposition creates a novel coding sequence containing parts of the coding sequences from two different genes. Naturally occurring fusion proteins are commonly found in cancer cells, where they may function as oncoproteins. The bcr-abl fusion protein is a well-known example of an oncogenic fusion protein, and is considered to be the primary oncogenic driver of chronic myelogenous leukemia.

Naturally occurring fusion genes are most commonly created when a chromosomal translocation replaces the terminal exons of one gene with intact exons from a second gene. This creates a single gene which can be transcribed, spliced, and translated to produce a functional fusion protein. Many important cancer-promoting oncogenes are fusion genes produced in this way.
Does MET have a known fusion protein?
Multiple mechanisms of dysregulation of receptor tyrosine kinases (RTKs) are observed in human cancers. In addition to gain-of-function, loss of negative regulation also contributes to oncogenic activation of RTKs. Negative regulation of many RTKs involves their internalization and degradation in the lysosome, a process regulated through ubiquitination. RTK oncoproteins activated following chromosomal translocation, are no longer transmembrane proteins, and are predicted to escape lysosomal degradation. To test this, we used the Tpr–Met oncogene, generated following chromosomal translocation of the hepatocyte growth factor receptor (Met). Unlike Met, Tpr–Met is localized in the cytoplasm and also lacks the binding site for Cbl ubiquitin ligases. We determined whether subcellular localization of Tpr–Met, and/or loss of its Cbl-binding site, is important for oncogenic activity. Presence of a Cbl-binding site and ubiquitination of cytosolic Tpr–Met oncoproteins does not alter their transforming activity. In contrast, plasma membrane targeting allows Tpr–Met to enter the endocytic pathway, and Tpr–Met transforming activity as well as protein stability are decreased in a Cbl-dependent manner. We show that transformation by Tpr–Met is in part dependent on its ability to escape normal downregulatory mechanisms. This provides a paradigm for many RTK oncoproteins activated following chromosomal translocation.
What is bcr-abl?
Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia (CML). It is the result of a reciprocal translocation between chromosome 9 and 22, and is specifically designated t(9;22)(q34;q11). The presence of this translocation is a highly sensitive test for CML, since 95% of people with CML have this abnormality (the remainder have either a cryptic translocation that is invisible on G-banded chromosome preparations, or a variant translocation involving another chromosome or chromosomes as well as the long arm of chromosomes 9 and 22). However, the presence of the Philadelphia (Ph) chromosome is not sufficiently specific to diagnose CML, since it is also found in acute lymphoblastic leukemia[1] (ALL, 25–30% in adult and 2–10% in pediatric cases) and occasionally in acute myelogenous leukemia (AML).
Why is the Philadelphia chromosome known as the Philadelphia chromosome?
The Philadelphia chromosome was first discovered and described in 1960 by Peter Nowell from University of Pennsylvania School of Medicine[8] and David Hungerford from the Fox Chase Cancer Center's[9] Institute for Cancer Research and was therefore named after the city in which both facilities are located.
How is HIF alpha broken down by the cell?
HIF-a is hydroxylated by prolyl
hydroxylase, marking it for ubiquitination by an E3 ubiquitin ligase complex that contains VHL. So if cells don't have VHL then the ubiquitin complex doesn't work and HIF alpha accumulates. In SDH tumors succinate competes for proly hydroxylate binding and inhibits HIF alpha degredation.
How is mTOR1 activated?
The mTORC1 complex is activated by
AKT which promotes mTORC1 by phosphorylation of the
tuberous sclerosis complex (TSC1/2) and activation of the
RHEB (Ras homolog enriched in brain) protein.
What are the downstream targets of mTOR1 and what are their functions?
The downstream
targets of mTORC1 are the p70-S6 Kinase 1 (S6K1)
and the translation initiation factor 4E binding protein
(4E-BP1), which is activated by mTOR and then dissociates
from the eukaryotic translation factor (eIF-4E) (7). The
activated form of S6K1 stimulates protein synthesis of
elongation and initiation factors and ribosomal proteins
required for the start of the S phase of the cell cycle
What is commonly described as a biomarker for mTOR activation?
The phosphorylation and activation of mTOR at Ser2448 is blocked by mTOR inhibitors depending on the AKT activation status

Chiang GG and Abraham RT:Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6
kinase. J Biol Chem 280: 25485-25490, 2005.
In the mTOR pathway what does RICTOR stand for in mTOR2?
Rapamycin insensitive companion of mTOR (RICTOR)
Is Temsirolimus ever considered first line therapy in metastatic kidney cancer patients?
In the clinic the mTOR inhibitor
temsirolimus proved beneficial and significantly enhanced
survival of mRCC patients (4). It is the recommended first
line treatment for patients with advanced mRCC and a poor
prognosis according to the Motzer score.
How is mTOR related to HIF?
The dissociation of 4E-BP1 from eIF-4E leads to cap-dependent messenger (mRNA) translation of c-Myc, cyclin D1, ornithine decarboxylase and hypoxia inducible factor (HIF).

Therefore the synthesis of HIF is regulated by mTOR, VHL has to do with the degredation of HIF.
So how is mTOR postulated to be activated in CCRCC, is it via increased protein expression or simply increased protein phosphorylation?
We hypothesized
that the activation of the mTOR signaling pathway in clear
cell RCC is caused by hyperphosphorylation of expressed
mTOR rather than through an increased protein expression.
For a better comparability of immunohistochemical results
between the samples, a tissue-microarray analysis was
performed. Decreased mTOR levels with corresponding
increased p-mTOR expression were found in RCC tissue
compared to benign kidney tissue
Is mTOR a tyrosine kinase or something else?
The serine/threonine kinase mammalian target of rapamycin
(mTOR)
What are downstream targets of mTOR2?
For instance, mTORC2 phosphorylates
AKT, SGK1 and PKC (members of the AGC kinase family) which control cell survival and cytoskeletal organization.

D.A. Guertin, D.M. Sabatini, Defining the role of mTOR in cancer, Cancer Cell 12
(2007) 9–22.
What are the 4E-BPs?
4E-BPs
are a family of small molecular weight translational repressors that include 4E-BP1, 4E-BP2, and 4E-BP3. 4E-BP1 is the most well known.
Does TOR1 inhibit or promote autophagy?
It inhibits autophagy and this makes sense because it is revving up the cell for growth and protein synthesis.
What are some genes that antagonize AKT activation of mTOR1?
mTORC1 signalling is frequently dysregulated in cancer [1,43]. Loss or inactivation of tumor suppressors such as p53, LKB1, PTEN, and TSC1/2, which antagonize PI3K-dependent activation of mTORC1, can promote tumorigenesis via increased signalling through mTORC1.

D.M. Sabatini, mTOR and cancer: insights into a complex relationship, Nat. Rev.
Cancer 6 (2006) 729–734.
[45] K. Inoki, T. Zhu, K.L. Guan, TSC2 mediates cellular energy response to control cell
growth and survival, Cell 115
How is it thought that mTORC2 is necessary for PTEN-dependent tumorigenesis?
In addition to the emerging role of mTORC2 in the activation of
AKT, it was recently shown that mTORC2 activity is necessary for
PTEN-dependent tumorigenesis. A study by Guertin at al., [75]
revealed that mTORC2 signalling is necessary for the development of prostate cancer caused by Pten deletion

D.A. Guertin, D.M. Stevens, M. Saitoh, S. Kinkel, K. Crosby, J.H. Sheen, D.J.
Mullholland, M.A. Magnuson, H. Wu, D.M. Sabatini, mTOR complex 2 is required
for the development of prostate cancer induced by Pten loss in mice, Cancer Cell
15 (2009) 148–159.
What does eIF stand for?
eukaryote initiation factor - required for starting protein synthesis.
Describe the process of PI3K activation and MTOR1 activation?
mTOR is only one part of the larger phosphatidylinositol 3
kinase (PI3K)/Akt/mTOR pathway (Figure 1). Upstream
activation of this pathway begins when growth factors
(insulin, insulin-like growth factor, platelet-derived
growth factor), mitogens, hormones, or nutrients activate
PI3K.20,22,23 PI3K is a heterodimer that consists of a catalytic
subunit (p110) and a regulatory subunit (p85, p55, or p50).22
The activated p110 catalytic subunit, encoded by the PIK3CA
gene, phosphorylates phosphatidylinositol bisphosphate4,5
on the inner leaflet of the cytoplasmic membrane to generate
phosphatidylinositol triphosphate (PIP3).3–5 PIP3 subsequently
binds to the pleckstrin homology domain of Akt1
kinase (also known as protein kinase B) to recruit Akt1 to the
cell membrane for phosphorylation.19,24 Akt1 is phosphorylated
at Threonine 308 by phosphoinositide-dependent
protein kinase 1 (PDK-1)25–27 and at Serine 473 (Ser473) by
PDK-2, which is believed to be rictor.9,14,19,27 Activated Akt1
inactivates the tuberous sclerosis complex (TSC) composed
of TSC1 and TSC2, by directly phosphorylating the
GTPase-activating protein TSC2. TSC2 and TSC1 normally
act together as tumor-suppressor proteins inhibiting cell
growth by negatively regulating the small GTPase-activating
protein Ras homolog enriched in brain (Rheb).14 When
released from TSC inhibition, Rheb is free to activate
mTORC1
What is IP?
Immunoprecipitation (IP) is the technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein. This process can be used to isolate and concentrate a particular protein from a sample containing many thousands of different proteins. Immunoprecipitation requires that the antibody be coupled to a solid substrate at some point in the procedure.
What is Co-IP and the pull down?
Immunoprecipitation of intact protein complexes (i.e. antigen along with any proteins or ligands that are bound to it) is known as co-immunoprecipitation (Co-IP). Co-IP works by selecting an antibody that targets a known protein that is believed to be a member of a larger complex of proteins. By targeting this known member with an antibody it may become possible to pull the entire protein complex out of solution and thereby identify unknown members of the complex.

This works when the proteins involved in the complex bind to each other tightly, making it possible to pull multiple members of the complex out of solution by latching onto one member with an antibody. This concept of pulling protein complexes out of solution is sometimes referred to as a "pull-down". Co-IP is a powerful technique that is used regularly by molecular biologists to analyze protein–protein interactions.
Your DMEM media after it has been around for a while turns purplish showing that it is more alkaline, and I had a problem in my incubator where the same problem was happening why is that?
Slightly higher pH (7.7) in the bottles of medium usually occurs due to loss of carbon dioxide when the bottles are opened or during storage. The pH increase is due to the nature of the bicarbonate-carbon dioxide buffering system; this increase is normal and completely reversible. Simply allow the medium time in the incubator to reach equilibrium with an atmosphere of 5% carbon dioxide. The proper way to check the pH is to place a 7mL sample of medium in an incubator in a loosely capped 15mL centrifuge tube for at least 60 minutes. Cap the tube and then immediately check the pH without allowing time for the medium sample to lose carbon dioxide. If the pH does not come down after equilibration in the incubator, you should check the functioning of the carbon dioxide regulation in the incubator.
How is it possible that mTORC2 and HIF-2alpha are related?
In addition,
mTOR signaling complex 2 (mTORC2), a known activator of
AKT signaling, has been shown to promote HIF-2a accumulation
in VHL null renal carcinoma cells [18]. More recently,
treatment of RCC cells with a dual PI3K/mTOR inhibitor
suppressed the expression of HIF-2a.

Sudarshan et al. 2011
What does STAT stand for?
Signal transduction and activator of transcription
What are the PDGFR family of kinases?
This is comprised of PDGFRalpha, PDGFR beta, and c-KIT, colony stimulating factor receptor 1, and flt-3.
ZD 2171 also known as Cedirinib inhibits what pathways?
Well the jury is still completely out, but it looks like a multi-TKI inhibitor. It inhibits VEGFR1, VEGFR2, VEGFR3, also it appears to inhibit PDGFRalpha, PDGFRbeta, and c-KIT.