Week 9 Flashcards
How was Bcl-2 discovered?
BCL2 was originally identified in Croce’s lab in 1984 as the target within the breakpoint region of the t(14;18) translocation carried by patients with the follicular variant of B-cell lymphoma, from which it takes its name
What does Bcl-2 do?
A protein that helps control whether a cell lives or dies by blocking a type of cell death called apoptosis
What are some members of the Bcl-2 family of proteins?
- Bcl-2 associated X protein
- Bcl-xL
- Bcl-2 homologous antagonist
- Bcl-2 associated death promoter
- Bcl2l2
- BECN1
- Voltage dependent anion channel
What are the guardians?
The anti-apoptotic
family members of Bcl-2
What are the effectors?
The pro-apoptotic family
members of Bcl-2
What are the locations of BAK and BAX?
Bax primarily localizes to the cytoplasm in healthy cells while Bak is mainly located at the MOM
What are the initiators?
The pro-apoptotic family members of Bcl-2
What can trigger the activation of apoptosis?
Either intrinsic cues or activation of the relevant pathways by external ligands
What do BAX and Bak bind to?
Bax and Bak can be activated by direct binding of certain BH3-only proteins
What are BAX and BAK known as?
The gateway to apoptosis because of their requisite roles as effectors of mitochondrial outer membrane permeabilization (MOMP), a major step during mitochondria-dependent apoptosis
What is the relationship between the Bcl2 family and cancer?
Overexpression of antiapoptotic BCL2 family proteins is observed in many cancers, and can result from chromosomal translocations, gene amplification, increased gene transcription, and/or altered posttranslational processing
What are BHS-mimetic drugs developed to do?
Directly activate the apoptosis machinery in malignant cells
What is ABT-737?
A small molecule drug that inhibits Bcl-2 and Bcl-xL, two members of the Bcl-2 family of evolutionarily-conserved proteins that share Bcl-2 Homology domains
What is Navitoclax?
An experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax
What are the common side effects of Navitoclax?
- a drop in blood cells causing an increased risk of infection, bleeding problems, tiredness and breathlessness.
- diarrhoea or constipation.
- feeling or being sick.
- tiredness (fatigue)
- loss of appetite
Is ABT-199 venetoclax?
Venetoclax (ABT-199): a Selective Inhibitor of B-Cell Lymphoma-2
How long does it take venetoclax to work?
In the clinical study, the median time for patients to achieve some level of remission for either CR or CRh was 1 month (with a range of 0.6 to 14.3 months)
What is a promising anti-tumor therapeutic?
BH3 mimetics targeting MCL-1
Where does extrinsic apoptosis begin?
Outside a cell, when conditions in the extracellular environment determine that a cell must die
What are death receptors?
Membrane-bound protein complexes that on binding their cognate ligand, activate an intracellular signaling cascade that results in apoptosis
What is disc in apoptosis?
The death-inducing signaling complex (DISC), composed of Fas, FADD, and caspase-8, is an apical signaling complex that mediates receptor-induced apoptosis
What is tBid?
A pro-apoptotic member of the Bcl-2 protein family
What is the role of caspase-8 in apoptosis?
It is required to allow mouse embryo survival, and the survival of hematopoietic cells during their development and activation
What treatments are typically associated with the increased markers of apoptosis?
In vitro and in vivo, effective treatment of cancer with radiotherapy or anticancer drugs
Where is the apoptotic “point of no return”?
It’s commonly held to be the point at which the outer mitochondrial membrane is permeabilised, a process regulated by the Bcl-2 family of proteins
What are the morphological characteristics of apoptosis?
Cell shrinking, chromatin condensation, nuclear fragmentation, and plasma membrane blebbing
Can apoptosis occur without caspases?
Although the biochemical changes explain in part some of the morphological changes in apoptosis, it is important to note that biochemical analyses of DNA fragmentation or caspase activation should not be used to define apoptosis, as apoptosis can occur without oligonucleosomal DNA fragmentation
What is a requirement of caspase-independent cell death linked with inflammation?
Mitochondrial DNA (mtDNA) activation of cGAS‐STING signalling
What does caspase do in apoptosis?
Caspases, a unique family of cysteine proteases, execute programmed cell death (apoptosis)
