Path: Hallmarks of Cancer 1 Flashcards
What is Rb protein?
a protein that can complex with E2F TF to block transcription of growth factors required for the S phase
What happens when RB is hypophosphorylated?
hypophosphorylated RB will complex with E2F TF; together they bind DNA and recruit chromatin-remodeling factors; this inhibits transcription of genes whose products are required for the S phase
What are the chromatin-remodeling factors recruited to block transcription by hypophosphorylated RB and E2F complex?
histone deacetylases and histone methyltransferases
What happens when RB is [hyper]phosphorylated?
it releases E2F and ill no longer block transcription
What cyclins phosphorylate RB?
D-CDK4, D-CDK6, and E-CDK2 complexes
What does E2F do when not bound to RB protein?
it acts as a TF and activates transcription of S phase genes
The phosphorylation of RB is inhibited by ________ because they inactivate ________ complexes.
cyclin-dependent kinase inhibitors; cyclin-CDK
Growth inhibitors activate ____, whereas growth factors activate ____. This leads to ____ and ____ RB, respectively.
CDKIs; cyclin-CDK complexes;
hypophosphorylated and hyperphosphorylated
Virtually all cancer cells show dysregulation in the ____ checkpoint as the result of a mutation in one of the four genes that regulate the phosphorylation of ____.
G1/S; RB
What are the 4 genes that regulate the phosphorylation of RB?
the genes encoding:
RB, CDK4, cyclin D proteins, CDKN2A (p16)
What state is RB in within active cells, and what state within inactive cells?
RB is in an active hypophosphorylated in quiescent cells; it’s in an inactive hyperphosphorylated in G1/S transitioning cells
Once a cell enters the S phase, is it obligated to complete mitosis?
Yes
What are the 2 manners in which RB function may be compromised?
- loss of function mutation involving both alleles
- shift from active to inactive state by gain-of-function mutations in the cyclin-CDK complexes OR loss of function in the CDKIs
What effect do some oncogenic viruses have on RB?
the virus binds hypophosphorylated RB in the same pocket that E2F would be, so E2F is free to go transcribe and cause cell cycle progression
What is the basis of HPV types that confer a high risk for development of cervical carcinoma versus a lower risk viral type?
the higher risk types express protein variants (E7 in the case of HPV) that will bind hypophosphorylated RB with greater affinity than E2F, and with greater affinity than other viral proteins
What does p53 do to DNA and the cell when active?
binds DNA in genetically damaged cells, arrests cell cycle for DNA repair, and initiated apoptosis if repair is impossible
How long it the p53 half-life, and what inactivates it?
half life is 20min and ubiquitin proteolysis ends p53
There is a bi-allelic loss of p53 in ___% of tumors.
70%. wow that’s a lot.
What do MDM2 and E6 (HPV proteins) do?
they degrade p53, which gives the virus resistance to p53
What component within cancer cells mediates the response to chemoradiotherapy and how?
p53 - because chemoradiotherapy introduces cell DNA mutations, and p53 is the one that is supposed to recognize and fix the damage, or apoptose the cell
What is TP53?
the name for the tumor suppressor gene that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis
____ is the most frequently mutated gene in cancer: loss-of-function mutations in TP53 are found in over ___% of cancers.
TP53; 50%
What are the 3 leading cancers that cause death?
lung, colon, and breast cancers
True or false: most TP53 mutations are inherited in germline cells.
False - most are acquired in somatic cells
One mutated allele for TP53 will do what?
predispose a person to develop a malignancy because only one additional “hit” to the one remaining normal allele is needed
What is Li-Fraumeni syndrome?
AD allele mutation in the TP53 gene that confers a 25-fold greater chance over the general population of developing malignancy by age 50
