Stem Cells and Cancer - Self-renewal Flashcards
What are two defining features of stem cells?
Ability to self-renew and their ability to give rise to committed progenitors of differentiated cell types of one or more cell lineages.
Self-renewal provides an extended window of time for
Mutations.
Stem cells are long-lived targets for chance mutations compared with many differentiated cells that die within days of months. The accumulation of mutations necessary for carcinogenesis is more likely to occur in stem cells that self-renew over the lifetime of an individual rather than in mature cells that exit the cell cycle and/or undergo apoptosis after a brief period.
Why does self-renewal allow for the accumulation of numerous mutations?
An individual mutation may be passed on to a daughter cell which itself is susceptible to mutations and can then pass these on to future progeny cells.
Stem cells must maintain a balance between self-renewal and differentiation. How may this be of relevance to carcinogenesis?
Loss of the balance by stem cells can lead to upregulated self-renewal, a hallmark of cancer.
Therefore, tumour cells may arise from stem cells.
Or, differentiated cells may acquire a mutation that reactivates a self-renewal program.
What other evidence is there for the role of cancer stem cells?
Several types of cancer tumours are maintained by only a small fraction of particular tumour cells.
These cells have surface markers indicative of the tissue stem cells.
For example, only about one in a million acute myeloid leukemia cells can develop into new leukemias when transferred in vivo.
Also these cells have the ability to give rise to cells with different characteristics or phenotypes that make up the bulk of the tumour.
What is believed to be one of the reasons that an early first full-term pregnancy is protective against developing breast cancer in later life?
The depletion of mammary stem cells that occurs during pregnancy is suggested as the reason why pregnancy is protective against BC.
What are Wnt proteins?
19 members.
Secreted intercellular signalling molecules that act as a ligand to trigger specific signal transduction pathways.
In the absence of Wnt ligands what is the state of the cell?
Several proteins associate together in the cytoplasm to form a degradation complex.
Axin + Adenomatous polyposis coli (APC) protein, glycogen synthase kinase (GSK3B), and casein kinase I (CKI).
B-catenin (transcriptional co-activator) is modified by this complex via sequential phosphorylation followed by ubiquitination via a newly recruited ubiquitin ligase. Flags B-catenin for degradation by proteosomes.
Thus, B-catenin is not available to associate with the TcF/LEF family of transcription factors. In the absence of B-catenin, TcF associates with the repressor Groucho.
When Wnt ligands are absent, what is the state of B-catenin?
Several proteins associate together in the cytoplasm to form a degradation complex.
Axin + Adenomatous polyposis coli (APC) protein, glycogen synthase kinase (GSK3B), and casein kinase I (CKI).
B-catenin (transcriptional co-activator) is modified by this complex via sequential phosphorylation followed by ubiquitination via a newly recruited ubiquitin ligase. Flags B-catenin for degradation by proteosomes.
In the absence of Wnt ligands, why is TcF associated with the transcriptional repressor Groucho?
Several proteins associate together in the cytoplasm to form a degradation complex.
Axin + Adenomatous polyposis coli (APC) protein, glycogen synthase kinase (GSK3B), and casein kinase I (CKI).
B-catenin (transcriptional co-activator) is modified by this complex via sequential phosphorylation followed by ubiquitination via a newly recruited ubiquitin ligase. Flags B-catenin for degradation by proteosomes.
Thus, B-catenin is not available to associate with the TcF/LEF family of transcription factors. In the absence of B-catenin, TcF associates with the repressor Groucho.
When Wnt is _______. Several proteins associate together in the cytoplasm to form a degradation complex.
They are: ____ + ___ + _____ + ___. This complex serves to modify _______ via sequential __________ followed by ___________ via newly recruited ubiquitin ligase. This has the effect of ________________________.
As a result, ________ is not available to associate with the ________ family of transcription factors. In the absence of ______, This family (___) associates with the repressor ________.
Several proteins associate together in the cytoplasm to form a degradation complex.
Axin + Adenomatous polyposis coli (APC) protein, glycogen synthase kinase (GSK3B), and casein kinase I (CKI).
B-catenin (transcriptional co-activator) is modified by this complex via sequential phosphorylation followed by ubiquitination via a newly recruited ubiquitin ligase. Flags B-catenin for degradation by proteosomes.
Thus, B-catenin is not available to associate with the TcF/LEF family of transcription factors. In the absence of B-catenin, TcF associates with the repressor Groucho.
Wnt binds to what receptor?
The seven-pass transmembrane receptor, Frizzled, and the co-receptor LRP - this disrupts the assembly of the degradation complex which normally degrades B-catenin.
Thus, B-catenin can move into the nucleus and act as a co-activator of the Tcf/LEF family of transcription factors to regulate specific target genes such as c-myc, cyclin D and genes that code for adhesion molecules from the EPH family.
Activation of these target genes also depends on nuclear proteins Bcl9 and Pygopus.
What happens when Wnt binds to its receptor?
The seven-pass transmembrane receptor, Frizzled, and the co-receptor LRP - this disrupts the assembly of the degradation complex which normally degrades B-catenin.
Thus, B-catenin can move into the nucleus and act as a co-activator of the Tcf/LEF family of transcription factors to regulate specific target genes such as c-myc, cyclin D and genes that code for adhesion molecules from the EPH family.
Activation of these target genes also depends on nuclear proteins Bcl9 and Pygopus.
What happens when Wnt binds to its receptor?
The seven-pass transmembrane receptor, Frizzled, and the co-receptor LRP - this disrupts the assembly of the degradation complex which normally degrades B-catenin.
Thus, B-catenin can move into the nucleus and act as a co-activator of the Tcf/LEF family of transcription factors to regulate specific target genes such as c-myc, cyclin D and genes that code for adhesion molecules from the EPH family.
Activation of these target genes also depends on nuclear proteins Bcl9 and Pygopus.
What are the target genes of B-catenin?
C-myc, Cyclin D, genes that code for adhesion molecules.
What does the activation of the target genes of B-catenin depend on, other than the presence of Wnt ligand binding to frizzled receptor?
The seven-pass transmembrane receptor, Frizzled, and the co-receptor LRP - this disrupts the assembly of the degradation complex which normally degrades B-catenin.
Thus, B-catenin can move into the nucleus and act as a co-activator of the Tcf/LEF family of transcription factors to regulate specific target genes such as c-myc, cyclin D and genes that code for adhesion molecules from the EPH family.
Activation of these target genes also depends on nuclear proteins Bcl9 and Pygopus.
How are B-catenin and E2F similar?
E2F is prevented from acting until pRB phosphorylated.
B-catenin is prevented from acting until Wnt pathway activation occurs.
Mutations that result in constitutive activation of the Wnt pathway are responsible for __% of colorectal cancer.
90%
Most of the mutations that result in constitutive activation of the Wnt pathway involve
- Inactivation of the function of APC (degradation complex, familial: adenomatous polyposis)
- activation of B-catenin.
What is famailial adenomatous polyposis coli caused by?
Germline mutation in the APC gene.
Develop high numbers of polyps in the colon in early adulthood.
Some of these then develop into colorectal cancer.
The APC gene acts a true tumour suppressor gene in that both copies of the APC gene are inactivated in colorectal tumours.
What is a well-studied model for examining the link between stem cells, the Wnt pathway and cancer?
The small intestine/colon.
Intestinal tissue is highly regenerative ; stem cells and epithelial progenitors, also called transit-amplifying cells that reside in the crypts give rise to more differentiated cells that migrate up along the villi.
What is Lgr5?
A target gene, encoding a G protein-coupled receptor, of the Wnt pathway that is located only in the stem cells of the intestine.
What is the ultimate molecular consequence of having inactivated mutations in APC?
Constitutive activation of TcF transcription factors.
The mutation cluster region of APC is where?
Located between 1250-1500 codons.
