Path Book: Chapter 5 Neoplasia pg. 178-190

Question 1

Carcinogenesis is a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype.

Answer 1

Many cancers arise from non-neoplastic precursor lesions, which molecular analyses have shown already possess some of the mutations needed to establish a full-blown cancer. Presumably these mutations provide the cells of the precursor lesion with a selective advantage. Once initiated, cancers continue to undergo darwinian selection.

Question 2

What are some phenotypic manifestations of malignant neoplasms?

Answer 2

excessive growth, local invasiveness, and the ability to form distant metastases.

Question 3

What is tumor progression?

Answer 3

Over a period of time, many tumors become more aggressive and acquire greater malignant potential.

Question 4

T or F. Increasing malignancy often is acquired in an incremental fashion.

Answer 4

T. At the molecular level, tumor progression and associated heterogeneity are most likely to result from multiple mutations that accumulate independently in different cells, generating subclones with different characteristics such as ability to invade, rate of growth, metastatic ability, etc

Some of the mutations may be lethal; others may spur cell growth by affecting proto-oncogenes or cancer suppressor genes.

Question 5

Thus even though most malignant tumors are monoclonal in origin, by the time they become clinically evident their con- stituent cells may be extremely heterogeneous.

Answer 5

Thus even though most malignant tumors are monoclonal in origin, by the time they become clinically evident their con- stituent cells may be extremely heterogeneous.

Question 6

During progression, how are tumor cells subjected to immune and nominate section pressures?

Answer 6

For example, cells that are highly antigenic are destroyed by host defenses, whereas those with reduced growth factor requirements are positively selected.

A growing tumor, therefore, tends to be enriched for subclones that “beat the odds” and are adept at survival, growth, invasion, and metastasis.

Question 7

What is a major significance of the selective pressure of tumors?

Answer 7

The recurrent tumor is almost always resistant to the drug regimen if it is given again.

Question 8

What are some of the hallmarks of cancer cell growth/behavior?

Answer 8

• Self-sufficiency in growth signals
• Insensitivity to growth inhibitory signals
• Evasion of cell death
• Limitless replicative potential
• Development of sustained angiogenesis
• Ability to invade and 
metastasize

Also, reprogramming of energy metabolism and evasion of the immune system

Question 9

How does normal cell growth/proliferation occur?

Answer 9

1. The binding of a growth factor to its specific receptor on the cell membrane
2. Transient and limited activation of the growth factor receptor, which in turn activates several signal- transducing proteins on the inner leaflet of the plasma membrane
3. Transmission of the transduced signal across the cytosol to the nucleus by second messengers or a cascade of signal transduction molecules
4. Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription
5. Entry and progression of the cell into the cell cycle, resulting ultimately in cell division

Question 10

All cells need growth factors to grow. Are most growth factors autocrine, paracrine, or endocrine?

Answer 10

paracrine- most cells that make growth factors don’t express their receptor. This prevents positive feedback loops in the cell

Question 11

How do cancer cells evade the growth factor requirement?

Answer 11

• Many acquire the ability to synthesize the same growth factors to which they are responsive. Similar autocrine loops are fairly common in many types of cancer.
• Cancer cells acquire growth self-sufficiency is by interaction with stroma. In some cases, tumor cells send signals to activate normal cells in the supporting stroma, which in turn produce growth factors that promote tumor growth.

Question 12

How can mutated growth receptors stimulate cancer formation?

Answer 12

Mutant receptor proteins deliver continuous mitogenic signals to cells, even in the absence of the growth factor in the environment.

However, mutated receptors are not very common causes of cancer formation

Question 13

Growth receptors still play a significant role in cancer formation even though mutation is not common. How?

Answer 13

More common than mutations is overexpression of growth factor receptors, which can render cancer cells hyperresponsive to levels of the growth factor that would not normally trigger proliferation.

Question 14

What the result of a mutated HER2/NEU receptor? Treatment? Prognosis?

Answer 14

The gene encoding a related receptor, HER2/NEU (ERBB2), is amplified in 25% to 30% of breast cancers and adenocarcinomas of the lung, ovary, and salivary glands.

These tumors are exquisitely sensitive to the mitogenic effects of small amounts of growth factors, and a high level of HER2/NEU protein in breast cancer cells is a harbinger of poor prognosis.

Treatment of breast cancer with anti- HER2/NEU antibody is an elegant example of “bench to bedside” medicine.

Question 15

What are RAS and ABL?

Answer 15

A relatively common mechanism by which cancer cells acquire growth autonomy is mutations in genes that encode various components of the signaling pathways down- stream of growth factor receptors.

These signaling proteins couple growth factor receptors to their nuclear targets. They receive signals from activated growth factor receptors and transmit them to the nucleus, either through second messengers or through a cascade of phosphorylation and activation of signal transduction molecules.

Question 16

RAS is the most commonly mutated proto- oncogene in human tumors.

Answer 16

RAS is the most commonly mutated proto- oncogene in human tumors.

Indeed, approximately 30% of all human tumors contain mutated versions of the RAS gene, and the frequency is even higher in some specific cancers (e.g., colon and pancreatic adenocarcinomas).

Question 17

What is RAS specifically?

Answer 17

a G-receptor coupled protein that is inactivated when bound to GDP and active when bound to GTP

Question 18

How are GRCPs like RAS inactivated?

Answer 18

Activated state is short-lived because the intrinsic GTPase activity of RAS hydrolyzes GTP to GDP, releasing a phosphate group and returning the protein to its quiescent GDP-bound state.

In its mutated (aka cancer causing) state, RAS can no longer be inactivated due to point mutations

Question 19

What is BRAF? What kind of cancer is its mutated form present in?

Answer 19

a GRCP that lies in the RAS/RAF/ERK/MAP kinase pathway, is mutated in more than 60% of melanomas.

Question 20

What is ABL?

Answer 20

a non–receptor-associated tyrosine kinase that functions as a signal transduction molecule.

Mutation is common with cancer formation

Question 21

How is ABL mutated in chronic myelogenous leukemia and certain acute leukemias?

Answer 21

A part of the ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22, where it fuses with part of the breakpoint cluster region (BCR) gene.

The BCR-ABL hybrid protein maintains the tyrosine kinase domain; the BCR domain self- associates, a property that unleashes a constitutive tyrosine kinase activity. Of interest, there is cross-talk between BCR-ABL and RAS pathways, since BCR-ABL protein activates all of the signals that are downstream of RAS.

Question 22

How would/could you treat chronic myelogenous leukemia?

Answer 22

BCR-ABL kinase inhibitors

Question 23

What is Gleevec?

Answer 23

imatinib mesylate (Gleevec) is a BCR-ABL kinase inhibitor used in cancer therapy

Question 24

What is oncogene addiction?

Answer 24

case in which a tumor is profoundly dependent on a single signaling molecule (such as BCR-ABL). Common in leukemia

remember: BCR-ABL fusion gene formation is an early, perhaps initiating, event that drives leukemo- genesis.

Question 25

T or F. The ultimate consequence of signaling through mutated oncoproteins such as RAS or ABL is inappropriate and continuous stimulation of nuclear tran- scription factors that drive the expression of growth- promoting genes.

Answer 25

T. Thus, in addition to growth factor pathway mutations, growth autonomy may thus be a consequence of mutations affecting genes that regulate transcription of DNA

Question 26

What are some important transcription factors/genes/proteins that play a role in cancer formation when mutated?

Answer 26

A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, function as transcription factors that regulate the expression of growth-promoting genes, such as cyclins. Of these, the MYC gene is involved most commonly in human tumors (the MYC gene makes MYC protein).

Question 27

What does the MYC protein do?

Answer 27

The MYC protein can either activate or repress the transcription of other genes. MYC also is a key regulator of intermediate metabolism, upregulating genes that promote aerobic glycolysis (Warburg effect) and the increased utilization of glutamine, two metabolic changes that are hallmarks of cancer cells.

Question 28

Which growth-factor promoting genes does/can MYC activate?

Answer 28

Cyclin- dependent kinases (CDKs). In contrast, they repress transcription of CDK inhibitors (CDKIs) Thus, dysregulation of MYC promotes tumorigenesis by increasing expression of genes that promote progression through the cell cycle and repressing genes that slow or prevent progression through the cell cycle.

Question 29

How is MYC affected in Burkitt lymphoma?

Answer 29

Dysregulation of the MYC gene resulting from a t(8;14) translocation occurs in Burkitt lymphoma, a B cell tumor.

Question 30

The replication of cells is stimulated by growth factors or by signaling from ECM components through integrins.

Answer 30

The replication of cells is stimulated by growth factors or by signaling from ECM components through integrins.

Question 31

What are the main checkpoints of the cell cycle?

Answer 31

The cell cycle has multiple checkpoints, particularly during emergence from G0 into G1 and the transition from G1 to S phase.

Question 32

The orderly progression of cells through the various phases of the cell cycle is orchestrated by ______.

Answer 32

CDKs, which are activated by binding to the cyclin The *CDK*–cyclin complexes phosphorylate crucial target proteins that drive the cell through the cell cycle.

Question 33

What happens to cyclin levels when they accomplish their task?

Answer 33

cyclin levels decline rapidly.

Question 34

What happens if cell surveillance mechanisms such as CDKIs sense that DNA is too damaged to complete a cell cycle?

Answer 34

If DNA damage is too severe to be repaired, the cells are eliminated by apoptosis, or enter a nonreplicative state called senescence, primarily through p53-dependent mechanisms. Mutations in genes regulating these checkpoints allow cells with damaged DNA to divide, producing daughter cells carrying mutations.

Question 35

Which CDK-cyclin complexes regulate entry into the S phase from G1? How?

Answer 35

cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 regulate the G1-to-S transition by phosphorylating the Rb protein (pRb).

Question 36

Which CDK-cyclin complexes are active in S phase?

Answer 36

Cyclin A–CDK2 and cyclin A–CDK1 are active in the S phase.

Question 37

Which CDK-cyclin complex is essential for the G2-to-M transition?

Answer 37

Cyclin B–CDK1

Question 38

What do INK4 CDKIs do? Members?

Answer 38

The so-called INK4 inhibitors, composed of p15, p16, p18, and p19, act on cyclin D–CDK4 and cyclin D–CDK6. The other family of three inhibitors, p21, p27, and p57, can inhibit all CDKs.

Question 39

All cancers appear to have genetic lesions that disable the G1-S checkpoint, causing cells to continually reenter the S phase. For unclear reasons, particular lesions vary widely in frequency across tumor types.

Answer 39

All cancers appear to have genetic lesions that disable the G1-S checkpoint, causing cells to continually reenter the S phase. For unclear reasons, particular lesions vary widely in frequency across tumor types.

Question 40

Mutation of which CDK is most common in neoplastic transformation?

Answer 40

CDK4. Mutations affecting cyclins B and E and other CDKs also occur, but they are much less frequent than those affecting cyclin CDK4.

Question 41

Specifically, which kinds of cancers is CDK4 mutation common in?

Answer 41

melanomas, sarcomas, and glioblastomas.

Question 42

Do oncogene proteins tend to promote cell growth and proliferation or the opposite?

Answer 42

growth and proliferation. TSGs do the opposite.

Question 43

What is RB?

Answer 43

The retinoblastoma gene (RB), the first tumor suppressor gene to be discovered (aka the cell cycle governor)

Question 44

Describe the prevalence of sporadic vs. hereditary retinoblastoma

Answer 44

Approximately 60% of retinoblastomas are sporadic, and the remaining ones are familial, the predisposition to develop the tumor being transmitted as an autosomal dominant trait.

Question 45

What is the two-hit hypothesis?

Answer 45

•Two mutations (hits) are required to produce retinoblas-toma. These involve the RB gene, which has been mapped to chromosomal locus 13q14. Both of the normal alleles of the RB locus must be inactivated (hence the two hits) for the development of retinoblastoma. • In familial cases, children inherit one defective copy of the RB gene in the germ line; the other copy is normal.

Question 46

At the patient level, is hereditary retinoblastoma dominant or recessive?

Answer 46

Dominant. Thus, you only need one mutated/absent allele to perpetuate transmission

Question 47

At the cellular level, is hereditary retinoblastoma dominant or recessive? Explain

Answer 47

Recessive. A child will be born with one messed up allele and then a somatic mutation is needed for disease In sporadic cases, both normal RB alleles are lost by somatic mutation in one of the retinoblasts. The end result is the same: a retinal cell that has lost both of the normal copies of the RB gene becomes cancerous. Thus, a cell heterozygous at the RB locus is not neoplastic. Tumors develop when the cell loses its normal RB gene copy and thus becomes homozygous for the mutant allele.

Question 48

Patients with retinoblastoma are at increased of developing what other cancers?

Answer 48

osteosarcomas and some soft tissue sarcomas.

Question 49

Where is RB protein expressed? What is its job?

Answer 49

The RB gene product is a DNA-binding protein that is expressed in every cell type examined, where it exists in an active hypophosphorylated state and an inactive hyperphosphorylated state. The importance of Rb lies in its regulation of the G1/S checkpoint, the portal through which cells must pass before DNA replication commences.

Question 50

What is the most important checkpoint of cell division? Why?

Answer 50

The transition from G1 to S because once cells cross the G1 checkpoint they can pause the cell cycle for a time, but they are obligated to complete mitosis.

Question 51

If a cell is damaged in G1, what can it do to escape the cell cycle?

Answer 51

In G1 cells can remove themselves entirely from the cell cycle, either temporarily (quiescence, or G0) or permanently (senescence).

Question 52

The initiation of DNA replication (S phase) requires what?

Answer 52

the activity of cyclin E/CDK2 complexes

Question 53

How is cyclin E activated (so that it can activate CDK2)?

Answer 53

It is dependent on the E2F family of transcription factors

Question 54

What prevents the E2F family of transcription factors from activating cyclin E in early G1?

Answer 54

Early in G1, Rb is in its hypophosphorylated active form, and it binds to and inhibits the E2F family of transcription factors, preventing transcription of cyclin E.

Question 55

How does hypophosphorylated Rb inhibit E2F factors? 2 ways

Answer 55

1) First, it sequesters E2F, preventing it from interacting with other transcriptional activators. 2) Second, Rb recruits chromatin remodeling proteins, such as histone deacetylases and histone methyltransferases, which bind to the promoters of E2F-responsive genes such as cyclin E. These enzymes modify chromatin at the promoters to make DNA insensitive to transcription factors like E2F.

Question 56

How is Rb phosphorylated?

Answer 56

Growth factor signaling leads to cyclin D expression and activation of cyclin D–CDK4/6 complexes. These complexes phosphorylate Rb, inactivating the protein and releasing E2F to induce target genes such as cyclin E. Expression of cyclin E then stimulates DNA replication and progression through the cell cycle.

Question 57

When are Rbs dephosphorylated again?

Answer 57

When the cells enter S phase, they are committed to divide without additional growth factor stimulation. During the ensuing M phase, the phosphate groups are removed from Rb by cellular phosphatases, regenerating the hypophosphorylated form of Rb.

Question 58

Would cyclin D be overexposed or underexposed in a tumor?

Answer 58

overexpressed

Question 59

Which four cell-cycle mediators are most mutated in human cancer?

Answer 59

CDKN2A (p16), cyclin D, CDK4, or Rb

Question 60

How does/can HPV cause cancer?

Answer 60

E7 protein binds to the hypophosphorylated form of Rb, preventing it from inhibiting the E2F transcription factors. Thus, Rb is functionally deleted, leading to uncontrolled growth.

Question 61

What is p53?

Answer 61

protein product of the p53-encoding tumor suppressor gene, TP53

Question 62

How does p53 prevent neoplastic event?

Answer 62

1) activation of temporary cell cycle arrest (termed quiescence), 2) induction of permanent cell cycle arrest (termed senescence), or 3) triggering of apoptosis. If Rb “senses” external signals, p53 can be viewed as a central monitor of internal stress, directing the stressed cells toward one of these three pathways.

Question 63

In healthy cells, is p53 around long? Why or why not?

Answer 63

In nonstressed, healthy cells, p53 has a short half-life (20 minutes) because of its association with MDM2, a protein that targets p53 for destruction.

Question 64

What happens in relation to MDM2/p53 when cells become 'stressed' via hypoxia, DNA damage, etc.

Answer 64

“sensors” that include protein kinases such as ATM (ataxia telangiectasia mutated) are activated. These activated complexes catalyze post-translational modifications in p53 that release it from MDM2 and increase its half-life and enhance its ability to drive the transcription of target genes.

Question 65

Hundreds of genes whose transcription is triggered by p53 have been found. These genes suppress neoplastic transformation by three mechanisms:

Answer 65

1) p53-mediated cell cycle arrest may be considered the primor- dial response to DNA damage 2) p53-induced senescence (permanent cell cycle arrest) 3) p53-induced apoptosis of cells with irreversible DNA damage is the ultimate protective mechanism against neoplastic

Question 66

How does p53 promote quiescence?

Answer 66

It occurs late in the G1 phase and is caused mainly by p53-dependent transcription of the CDKI gene CDKN1A (p21). The p21 protein inhibits cyclin–CDK complexes and prevents phosphorylation of Rb, thereby arresting cells in the G1 phase for repair.

Question 67

What happens if DNA repair following quiescence is successful?

Answer 67

If DNA damage is repaired successfully, p53 upregulates transcription of MDM2, leading to destruction of p53 and relief of the cell cycle block.

Question 68

What happens if DNA repair following quiescence is not successful?

Answer 68

If the damage cannot be repaired, the cell may enter p53-induced senescence or undergo p53-directed apoptosis

Question 69

What occurs in senescence?

Answer 69

The mechanisms of senescence are unclear but seem to involve global chromatin changes, which drastically and permanently alter gene expression.

Question 70

Until recently it was thought that the functions of p53 were mediated exclusively by transcriptional activation of genes with antiproliferative, apoptotic, and senescence- inducing functions. But p53 also represses a subset of pro-proliferative and anti-apoptotic genes as well. How could p53, a transcriptional activator, repress gene function?

Answer 70

p53 can transcriptionally activate certain miRNAs. MiRNAs activated by p53 can inhibit the translation of pro- proliferative genes such as cyclins and anti-apoptotic genes such as BCL2.

Question 71

Confirming the importance of TP53 in controlling carci- nogenesis, more than 70% of human cancers have a defect in this gene, and the remaining malignant neoplasms have defects in genes upstream or downstream of TP53.

Answer 71

Confirming the importance of TP53 in controlling carci- nogenesis, more than 70% of human cancers have a defect in this gene, and the remaining malignant neoplasms have defects in genes upstream or downstream of TP53.

Question 72

Are most TP53 mutation sporadic or inherited?

Answer 72

sporadic

Question 73

What is a disease caused by inherited TP53 defect?

Answer 73

Li-Fraumeni syndrome. As with the RB gene, inheritance of one mutant allele predisposes affected persons to develop malignant tumors because only one additional hit is needed to inactivate the second, normal allele. Patients with the Li-Fraumeni syndrome have a 25-fold greater chance of developing a malignant tumor by age 50 compared with the general population and will typically develop multiple tumors

Question 74

What kinds of cancers are common in Li-Fraumeni syndrome?

Answer 74

In contrast with tumors developing in patients who inherit a mutant RB allele, the spectrum of tumors that develop in patients with the Li-Fraumeni syndrome is varied; the most common types are: sarcomas, breast cancer, leukemia, brain tumors, and carcinomas of the adrenal cortex.

Question 75

Which viruses can target p53?

Answer 75

Proteins encoded by oncogenic HPVs, hepatitis B virus (HBV), and possibly Epstein-Barr virus (EBV) can bind to normal p53 and nullify its protective function.

Question 76

What is a well known signal that transmits anti-proliferative signals to cells?

Answer 76

TGF-B. At some point, however it will actually help growth of a tumor via immunosuppression and by inducing VEGF (angiogenesis).

Question 77

What does TGF-B do to prevent proliferation?

Answer 77

In most normal epithelial, endothelial, and hematopoietic cells, TGF-β is a potent inhibitor of proliferation. It regulates cellular processes by binding to a complex composed of TGF-β receptors I and II. Dimerization of the receptor upon ligand binding leads to a cascade of events that result in the transcriptional activation of CDKIs with growth-suppressing activity, as well as repression of growth-promoting genes such as MYC, CDK2, CDK4, and those encoding cyclins A and E.

Question 78

What are the major mutation targets of the TGF-B pathway?

Answer 78

TGF-B receptor II and SMAD4, 1 of 10 proteins involved in TGF-B signal transduction

Question 79

Mutations affecting the type II receptor are seen in cancers of the ____, ____, and _____.

Answer 79

colon, stomach, and endometrium.

Question 80

In what condition is SMAD4 commonly mutated?

Answer 80

common in pancreatic cancers. NOTE: In 100% of pancreatic cancers and 83% of colon cancers, at least one component of the TGF-β pathway is mutated.

Question 81

What is “contact inhibition”?

Answer 81

When nontransformed cells are grown in culture, they pro- liferate until confluent monolayers are generated; cell–cell contacts formed in these monolayers suppress further cell proliferation. This is absent in tumor growth, allowing stacking to occur

Question 82

What protein does the gene NF2 make?

Answer 82

neurofibromin-2, more commonly called merlin

Question 83

What does merlin do?

Answer 83

facilitates E-cadherin mediated contact inhibition. E-cadherin is a major player in cell-cell contact loss of E-cadherin is common in lobular carcinoma of the breast.

Question 84

Homozygous loss of NF2 can cause in what?

Answer 84

A form of neural tumors associated with the condition called neurofibromatosis.

Question 85

What does the APC gene do?

Answer 85

exerts antiproliferative actions by regulating the destruction of the cytoplasmic protein β-catenin. With a loss of APC, β-catenin is not destroyed, and it translocates to the nucleus, where it acts as a growth-promoting trans-cription factor via the WNT signaling pathway.

Question 86

Loss of both copies of the APC gene result in what?

Answer 86

In familial adenomatous polyposis syndrome, inheritance of a germ line mutation in the APC gene and sporadic loss of the sole normal allele causes the development of hundreds of colonic polyps at a young age. Inevitably, one or more of these polyps evolves into a colonic cancer. Somatic loss of both alleles of the APC gene is seen in approximately 70% of sporadic colon cancers.

Question 87

How does the apoptotic pathway work?

Answer 87

The apoptotic pathway can be divided into upstream regulators and downstream effectors. The regulators are divided into two major pathways, one interpreting extracellular or extrinsic signals and the other interpreting intra- cellular signals. Stimulation of either pathway results in activation of a normally inactive protease (caspase-8 or caspase-9, respectively), which initiates a proteolytic cascade involving “executioner” caspases that disassemble the cell in orderly fashion. The cellular remains are then efficiently consumed by the cellular neighbors and profes- sional phagocytes, without stimulating inflammation.

Question 88

How is the extrinsic (death receptor) pathway initiated?

Answer 88

when a TNF receptor, such as CD95 (Fas), is bound to its ligand, CD95L, leading to trimerization of the receptor and its cytoplasmic death domains, which attract the intracellular adaptor protein FADD.

Question 89

What does FADD do?

Answer 89

This protein recruits procaspase-8 to form the death-inducing signaling complex. Procaspase-8 is activated by cleavage into smaller subunits, generating caspase-8.

Question 90

What does Caspase-8 do?

Answer 90

then activates downstream caspases such as caspase-3, an executioner caspase that cleaves DNA and other substrates to cause cell death.

Question 91

The intrinsic (mitochondrial) pathway of apoptosis is triggered by a variety of stimuli, including withdrawal of survival factors, stress, and injury. Activation of this pathway leads to what?

Answer 91

permeabilization of the mitochondrial outer membrane and release of molecules, such as cytochrome c, that initiate apoptosis.

Question 92

The integrity of the mitochondrial outer membrane is regulated by pro-apoptotic and anti-apoptotic members of the BCL2 family of proteins. How does this work?

Answer 92

The pro-apoptotic pro- teins BAX and BAK are required for apoptosis and directly promote mitochondrial permeabilization. Their action is inhibited by the anti-apoptotic members of this family exemplified by BCL2 and BCL-XL.

Question 93

What do BH3-only proteins, which include BAD, BID, and PUMA do?

Answer 93

The BH3-only proteins promote apoptosis by neutralizing the actions of anti-apoptotic proteins like BCL2 and BCL-XL. When the sum total of all BH3 proteins expressed “overwhelms” the anti-apoptotic BCL2/ BCLXL protein barrier, BAX and BAK are activated and form pores in the mitochondrial membrane, causing cytochrome c leaks into the cytosol Because of the pro-apoptotic effect of BH3 only proteins, efforts are underway to develop BH3 mimetic drugs to promote death of tumor cells.

Question 94

What does cytochrome c in the cytosol do?

Answer 94

binds to APAF-1 to activate caspase-9.

Question 95

What does caspase-9 do?

Answer 95

Like caspase-8 of the extrinsic pathway, caspase-9 can cleave and activate the executioner caspases.

Question 96

How can caspases be inhibited besides not getting their appropriate cell-death signals?

Answer 96

by a family of proteins called inhibitor of apoptosis proteins (IAPs).

Question 97

How can tumors evade the apoptotic pathway?

Answer 97

via upregulation of BCL2

Question 98

How is Bcl2 unregulated?

Answer 98

Approximately 85% of B cell lymphomas of the follicular type carry a characteristic t(14;18) (q32;q21) translocation. As noted earlier, 14q32, the chromosomal locus for immunoglobulin heavy-chain genes, also is involved in the pathogenesis of Burkitt lymphoma. Juxtaposition of this transcriptionally active locus with BCL2 (located at 18q21) causes overexpression of the BCL2 protein. This overabundance in turn increases the BCL2/ BCL-XL buffer, protecting lymphocytes from apoptosis and allowing them to survive for long periods; there is therefore a steady accumulation of B lymphocytes, resulting in lymphadenopathy and marrow infiltration. Because BCL2- overexpressing lymphomas arise in large part through reduced cell death rather than explosive cell proliferation, they tend to be indolent (slow-growing) compared to other lymphomas. In some instances, reduced levels of CD95 may render the tumor cells less susceptible to apoptosis by Fas ligand (FasL).

Question 99

What is FLIP?

Answer 99

Some tumors have high levels of FLIP, a protein that can bind death-inducing signaling complex and prevent activation of caspase 8.

Question 100

How is autophagy performed?

Answer 100

During autophagy, cellular organelles are sequestered from the rest of the cell by an autophagosome and then fused to a lysosome, where they are degraded and utilized for cellular energy generation. Later, tumors can use autophxgy by supplying the nutrients needed for survival in nutrient-poor environments