Flashcards in Hallmarks Deck (69)
The Big 8 - Hallmarks of Cancer
1) Avoiding immune destruction2) Evading growth suppressors3) Enabling replicative immortality4) Activating invasion and metastasis5) Inducing angiogenesis6) Resisting cell death7) De-regulating cellular energetics8) Sustaining proliferative signaling
A governor of proliferation and differentiationA key negative regulator of the G1-S transitionCancer inactivates it => two possible ways:1) loss-of-function mutation involving both Rb alleles2) A shift from the active, hypo-phosphorylated state to the inactive, hyper-phosphorylated state by gain-of-function mutations that up-regulate CDK/cyclin D activity or by loss-of-function mutations that inhibit CDK inhibitors
Hypo-phosphorylated Rb in complex with E2F transcription factor means what for the cell cycle?
This complex inhibits transcription of genes whose products are required for the S phase of the cell cycle.
Phosphorylation of Rb: process and consequence
Rb is phosphorylated by cyclin D/CDK4, cyclin D/CDK6, and cyclinE/CDK2 complexes. When these complexes phosphorylate Rb, they are inhibiting it from keeping hold of E2F.Upon phosphorylation, Rb releases the E2F transcription factor.E2F activates the transcription of S-phase genes.
Who inhibits phosphorylation of Rb?
Cyclin-dependent kinase inhibitors phosphorylate Rb indirectly because CDKIs inhibit cyclin-CDK complexes, which are the complexes that phosphorylate RB.
What does an active Rb look like, and where is it found?
A active Rb is hypo-phosphorylated, attached to E2F, and found in quiescent cells.
What does an inactivate Rb look like, and where is it found?
An inactive Rb is hyper-phosphorylated, thanks to high levels of the cyclinD/CDK4, cyclinD/CDK6, and cyclinE/CD2 complexes (these complexes are up-regulated by growth factors). It has released the E2F transcription factor.It is found in cells passing through the G1/S cell cycle transition.
Growth factor signaling pathway vs. Growth inhibition signaling pathwayWhat does Rb have to do with these pathways?
Growth factors up-regulate the cyclins and CDKs required for transitioning through phases in the cell cycle, whereas growth inhibitors up-regulate CDKIs to stop progression through cell cycle phases. Rb is the point of integration of these opposing signals, making it the key regulator of cell cycle progression.
According to current cancer data, which molecules are typically mutated or affected in patients with cancer?
p16/INK4acyclin DCDK4RbEither these guys have mutations, or they are affected by an abnormal molecule upstream of them in the signaling pathway (meaning they're normal, but cannot be activated/deactivated due to the struggler ahead in line).
What can oncogenic viruses do to Rb?Example?
The viral protein can bind to Rb, functionally inhibiting it so that it can no longer act as a cell cycle inhibitor (it can no longer hold on to E2F because the virus took that spot, so E2F goes off and transcribes things needed for the S phase of the cell cycle).Example: HPV types express a protein called E7 that binds with higher affinity to Rb than E2F does, leading to a high risk for cervical carcinoma.
blue 52! blue 52! Who p53?
Ye ol' p53 is the guardian of the genome and the central monitor of stress in the cell.Activated by anoxia, inappropriate signaling by mutated oncoproteins, or DNA damageMany jobs: 1) Prevents propagation of genetically damaged cells2) Binds to DNA3) Arrests cell cycle for DNA repair4) Initiates apoptosis if repair impossibleHe lives only for half-life of 20 minutes and is killed by ubiquitin proteolysis.
Is p53 affected in patients with tumors? If so, how?
Yes, it most certainly can be affected; 70% of the time there is bi-allelic loss of p53.Example: HPV expresses E6 protein, which degrades p53 (recall there is also an E7 protein associated with HPV).
A tumor suppressor gene that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosisA gene that encodes p53.The most frequently mutated gene in cancer; found in 50% of cancersMutation is not usually inherited, so it's found in somatic cells, with both alleles of the gene mutated.
The syndrome you have when you DO end up inheriting a mutated TP53 allele.You have a 25-fold greater chance of getting cancer because you're now just one mutation away from inactivating TP53
An inhibitor of p53. Phosphorylation of p53 releases it from the clutches of MDM2It is over-expressed in 33% of malignancies. It stimulates the degradation of p53.
E6 and E7
Proteins expressed by HPV that bind to RB with higher affinity than E2F, causing inactivation of RB and therefore progression of cell cycle to S phase, as E2F is now free to transcribe the proteins required.
p53 is a transcription factor. The key target genes that execute the functions of p53 are not really defined, but tend to fall in three categories:p53 also affects genes that encode two kinds of regulator RNA. What are they?
KEY TARGET GENES1) those that cause cell cycle arrest2) those that cause apoptosis3) those that enhance catabolic metabolism or inhibit anabolic metabolismREGULATORY RNA1) micro-RNA (mIRs)2) long intervening noncoding RNAs (LINC RNAs)These help to coordinate the p53-dependent cellular response to stress.
How is DNA damage sensed?
Damage is sensed by complexes containing the kinases of the ATM/ATR family. The kinases phosphorylate p53, freeing it from inhibitors such as MDM2.Active p53 up-regulates p21, a CDKI that inhibits cell cycle progression to the S-phase, standing guard at the G1/S checkpoint.DNA repair can now occur during the pause in cell cycle progression. Hopefully, for the cell's sake. If no, then bye-bye cell, 'ello apoptosis!
Von Hippel Lindau
A gene product that causes ubiquination and degradation of hypoxia inducible transcription factor-1.Result: Increased PDGF and VEGF => tumor angiogenesis.
Adenomatous polyposis coli (APC) and consequence of its germline loss-of-function mutation
A tumor suppressor that down-regulates growth-promoting signaling pathways.Molecular Consequence: loss of APC causes cells to behave as if they're continuously stimulated by WNT.Clinical Mutation Consequence: Familial adenomatous polyposis, an autosomal dominant disorder in which people born with one mutant allele develop thousands of polyps in the colon, one or more of which will invariably undergo mutant transformation, giving rise to colon cancer IF the other allele also ends up suffering a mutation.
Does APC really have anything to do with colorectal carcinomas?
Fo sho'. 70% of non-familial colorectal carcinomas and sporadic adenomas show acquired defects in both APC genes; thus, APC loss-of-function mutations are important in the formation of colonic tumors.
General relationship between Wnt/Frizzled, APC, and B-catenin
Wnt/Frizzled sends a signal to APCAPC responds by failing to form a proteosomal degradation complex to degrade B-catenin.B-catenin heads to nucleus, forms a complex with DNA binding factor TCF, and they together promote colonic epithelial cell growth
Consequence of loss of APC or lack of Wnt signaling to APC
If Wnt does not send signals to APC, APC forms a complex that degrades B-catenin. B-catenin can no longer promote colonic epithelial cell growth. If lack APC, as many colorectal patients do, APC is not available to degrade B-catenin, and unfettered proliferation of colonic epithelial cell growth results. Dysregulation of APC plays a role in cancers other than colorectal.
A proto-oncoprotein that plays a role in colonic epithelial cell growth.A gain-of-function mutation could lead to hepatoblastoma or hepatocellular carcinomas.If APC is lost (it is upstream of B-catenin in signaling process), then it can also enjoy unfettered cell proliferation.
The relationship between B-catenin and E-cadherin. How can their relationship lead to cancer?
E-cadherin maintains cellular adhesiveness. B-catenin is bound to E-cadherin. Their association is disrupted upon injury or trauma. In response, B-catenin heads to the nucleus, where it stimulates genes that promote proliferation that help with wound repair. Once repair is finished, B-catenin re-associates with E-cadherin and therefore remains sequestered in the cell membrane; this means these cells are "contact-inhibited". In the words of Dr. Nichols, "This is good."Cancer: Loss-of-contact inhibition or mutation of the E-cadherin/B-catenin complex can lead to cancer. Loss of E-cadherin (and therefore cell adhesion) also allows easy disaggregation of cells, which means that they can then head out to another site and invade (or invade locally).
What is the consequence of reduced cell surface expression of E-cadherin?
Carcinoma, especially in esophagus, colon, breast, ovary, and prostate.
The E-cadherin geneA germline loss-of-function mutation in this gene causes familial gastric carcinoma.
TGF-B: Normal and Cancer
Normally an inhibitor of proliferation1) Bind TGF-B receptors I and II, causing them to dimerize2) Dimerization initials intracellular signals (involving the SMAD family of proteins) that turn ON anti-proliferative genes and turn OFF proliferative genes.3)T These changes result in hypo-phosphorylation of Rb, causing it to hang on to E2F. …But also a double-edged sword that can promote or prevent tumor growth1) Loss-of-function mutation in the TGF-B signaling pathway2) Mutations in TGF-B II receptor that lead to cancers of the colon, stomach, and endometrium3) Mutational inactivation of SMAD4 leads to pancreatic cancer4) Loss of TGF-B mediated growth inhibition via mutations causing loss of p21 or sustained expression of MYC (MYC is a growth promoter)5) Sometimes preserved elements of TGF-B can allow for immune evasion and angiogenesis.
A membrane-associated phosphatase that acts as a tumor suppressor by serving as a brake on the P13K/AKT arm of the receptor tyrosine kinase pathway.Gene function can be lost through deletion, deleterious point mutations, or epigenetic silencing; seen notoriously in endometrial carcinoma.Can be mutated, causing Cowden syndrome