Pathology (neoplasia 4/molecular basis)

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Pathology (neoplasia 4/molecular basis)
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2013-10-16 10:17:28
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Pathology neoplasia molecular basis
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Pathology (neoplasia 4/molecular basis)
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  1. INSENSITIVITY TO GROWTH INHIBITION AND ESCAPE FROM SENESCENCE in tumors is a hallmark of  ....................
    mutations in TUMOR SUPPRESSOR GENES
  2. expression of an oncogene in an otherwise completely normal cell leads to .............................................
    quiescence, or to permanent cell cycle arrest (oncogene-induced senescence), rather than uncontrolled proliferation
  3. Another set of tumor suppressors seem to be involved in cell differentiation, causing cells to enter ....................................
    a postmitotic, differentiated pool without replicative potential
  4. The protein products of tumor suppressor genes may function as
    • transcription factors
    • cell cycle inhibitors
    • signal transduction molecules
    • cell surface receptors
    • regulators of cellular responses to DNA damage.
  5. What are the major tumor suppressor genes based on cell compartment?
    • Cell surface--> TGBR, E-Cadherin
    • Inner aspect of plasma membrane-->NF1
    • Cytoskeleton--> NF2
    • Cytosol-->APC/β-catenin, PTEN, SMAD2 and 4
    • Nucleus-->RB1,P53,WT1,P16/INK4a, BRCA1,2
  6. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of TGFBR
    Growth inhibition/ Carcinomas of colon/ Unknown
  7. Function/   Tumors Associated with Somatic    Mutations/ Tumors Associated with Inherited Mutations Of E-Cadherin
    Cell adhesion/ Carcinoma of stomach/ Familial gastric cancer
  8. Function/   Tumors Associated with Somatic    Mutations/ Tumors Associated with Inherited Mutations Of NF1
    Inhibition of RAS signal transduction and of p21 cell cycle inhibitor/ Neuroblastomas/ Neurofibromatosis type 1 and sarcomas
  9. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of NF2
    Cytoskeletal stability/ Schwannomas and meningiomas/ Neurofibromastosis type 2, acoustic schwannomas, and meningiomas
  10. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of APC/β-catenin
    Inhibition of signal transduction/ Carcinomas of stomach, colon, pancreas; melanoma/ Familial adenomatous polyposis coli/colon cancer
  11. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of PTEN
    PI3 kinase signal transduction/ Endometrial and prostate cancers/ Cowden syndrome
  12. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of SMAD2 and SMAD4
    TGF-β signal transduction/ Colon, pancreas tumors/ Unknown
  13. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of RB1
    Regulation of cell cycle/ Retinoblastoma; osteosarcoma carcinomas of breast, colon, lung/ Retinoblastomas, osteosarcoma
  14. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of P53
    Cell cycle arrest and apoptosis in response to DNA damage/ Most human cancers/ Li-Fraumeni syndrome; multiple carcinomas and sarcomas
  15. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of WT1
    Nuclear transcription/ Wilms' tumor/ Wilms' tumor
  16. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of P16/INK4a
    Regulation of cell cycle by inhibition of cyclindependent kinases/ Pancreatic, breast, and esophageal cancers/ Malignant melanoma
  17. Function/   Tumors Associated with Somatic   Mutations/ Tumors Associated with Inherited Mutations Of BRCA1/2
    DNA repair/ Unknown/ Carcinomas of female breast and ovary; carcinomas of male breast
  18. What is the sporadic/familial distribution of retinoblastoma?
    Approximately 60% of retinoblastomas are sporadic, and the remaining are familial, with the predisposition to develop the tumor being transmitted as an autosomal dominant trait
  19. What is the two-hit theory regarding RB?
    • Two mutations (hits), involving both alleles of RB at chromosome locus 13q14, are required to produce retinoblastoma. In some cases, the genetic damage is large enough to be visible in the form of a deletion of 13q14.  
    • In familial cases, children inherit one defective copy of the RB gene in the germ line (one hit); the other copy is normal ( Fig. 7-30 ). Retinoblastoma develops when the normal RB allele is mutated in retinoblasts as a result of spontaneous somatic mutation (second hit). Because only a single somatic mutation is required for loss of RB function in retinoblastoma families, familial retinoblastoma is inherited as an autosomal dominant trait.  
    • In sporadic cases both normal RB alleles must undergo somatic mutation in the same retinoblast (two hits). The end result is the same: a retinal cell that has completely lost RB function becomes cancerous
  20. True or False: A child carrying an inherited mutant RB allele in all somatic cells is perfectly normal (except for the increased risk of developing cancer)
    True
  21. one or more genes on the short arm of chromosome 11 play a role in the formation of ....................................
    Wilms' tumor, hepatoblastoma, and rhabdomyosarcoma
  22. RB exists in an............. in quiescent cells and an ...................... in the G1/S cell cycle transition
    active hypophosphorylated state/inactive hyperphosphorylated state
  23. True or False: Once cells cross the G1 checkpoint  they are obligated to complete mitosis
    True
  24. In ......, cells can exit the cell cycle, either temporarily, called quiescence, or permanently, called senescence
    G1
  25. The importance of RB lies in its enforcement of .....phase
    G1
  26. The initiation of DNA replication requires the activity of which cyclin/CDK?
    cyclin E–CDK2
  27. How does RB control cell cycle?
    • The initiation of DNA replication requires the activity of cyclin E–CDK2 complexes, and expression of cyclin E is dependent on the E2F family of transcription factors.
    • 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.
    • Hypophosphorylated RB blocks E2F-mediated transcription in at least two ways.
    • First, it sequesters E2F, preventing it from interacting with other transcriptional activators. 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 so as to make promoters insensitive to transcription factors.
    • Mitogenic 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.
    • 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.
    • E2Fs are not the sole effectors of Rb-mediated G1 arrest.
    • Rb also controls the stability of the cell cycle inhibitor p27
    • Hypophosphorylated RB in complex with the E2F transcription factors binds to DNA, recruits chromatin-remodeling factors (histone deacetylases and histone methyltransferases), and inhibits transcription of genes whose products are required for the S phase of the cell cycle.
    • When RB is phosphorylated by the cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 complexes, it releases E2F. The latter then activates transcription of S-phase genes.
    • The phosphorylation of RB is inhibited by CDKIs, because they inactivate cyclin-CDK complexes. Virtually all cancer cells show dysregulation of the G1-S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of RB; these genes are RB1, CDK4, the genes encoding cyclin D proteins, and CDKN2A (p16).
  28. Virtually all cancer cells show dysregulation of the ....... checkpoint as a result of mutation in
    • G1/S
    • one of four genes that regulate the phosphorylation of RB; these genes are RB1, CDK4, the genes encoding cyclin D proteins, and CDKN2A (p16).
  29. The mutations of RB genes found in tumors are localized to ............................................................
    a region of the RB protein, called the “RB pocket,” that is involved in binding to E2F
  30. What are other functions of RB in addition to G1/S control?
    • RB protein has also been shown to bind to a variety of other transcription factors that regulate cell differentiation. For example, RB stimulates myocyte-, adipocyte-, melanocyte-, and macrophage-specific transcription factors. Thus, the RB pathway couples control of cell cycle progression at G1 with differentiation, which may explain how differentiation is associated with exit from the cell cycle.
    • RB can also induce senescence
  31. why the loss of RB is not more common in human tumors?
    Mutations in other genes that control RB phosphorylation can mimic the effect of RB loss, and such genes are mutated in many cancers that may have normal RB genes
  32. Why do patients with germline mutation of the RB locus develop mainly retinoblastomas?
    RB family members may partially complement its function in cell types other than retinoblasts.
  33. at least one of four key regulators of the cell cycle ................................ is dysregulated in the vast majority of human cancers
    • p16/INK4a
    • cyclin D
    • CDK4
    • RB
  34. How is RB inactivated by viruses?
    • Simian virus 40 and polyomavirus large T antigens, adenoviruses EIA protein, and HPV E7 protein all bind to the hypophosphorylated form of RB.
    • The binding occurs in the same RB pocket that normally sequesters E2F transcription factors
  35. ............... is the most common target for genetic alteration in human tumors
    P53
  36. What are the oncogenes/tumor suppressors and CDK/cyclin complexes most commonly involved in cancer?
    • RAS
    • P53
    • Cyclin D/CDK4
  37. The p53 gene is located on chromosome
    17p13
  38. True or False:  Homozygous loss of p53 occurs in virtually every type of cancer
    True
  39. what are the most common tumors in Li-Fraumeni syndrome?
    Sarcomas, breast cancer, leukemia, brain tumors, and carcinomas of the adrenal cortex
  40. 80% of the p53 point mutations present in human cancers are located in the .....................
    DNA-binding domain of the protein
  41. True or False: P53 is a TF
    True
  42. .........is amplified in 33% of human sarcomas, thereby causing functional loss of p53 in these tumors.
    MDM2
  43. Which proteins stimulate P53 degradation?
    MDM2 and MDMX
  44. True or False: in the majority of tumors without a p53 mutation, the function of the p53 pathway is blocked by mutation in another gene that regulates p53 function
    True
  45. How does p53 thwart neoplastic transformation by three interlocking mechanisms?
    • Activation of temporary cell cycle arrest (quiescence)
    • Induction of permanent cell cycle arrest (senescence)
    • Triggering of programmed cell death (apoptosis)
  46. What are the statuses of P53 in stressed and nonstressed cells?
    • In nonstressed, healthy cells, p53 has a short half-life (20 minutes), because of its association with MDM2, a protein that targets it for destruction.
    • When the cell is stressed, for example by an assault on its DNA, p53 undergoes post-transcriptional modifications that release it from MDM2 and increase its half-life.
    • Unshackled from MDM2, p53 also becomes activated as a transcription factor
  47. What are the genes whose transcription are activated by P53?
    • They can be grouped into two broad categories: those that cause cell cycle arrest and those that cause apoptosis.
    • If DNA damage can be repaired during cell cycle arrest, the cell reverts to a normal state; if the repair fails, p53 induces apoptosis or senescence
  48. How does P53 repress a subset of pro-proliferative and anti-apoptotic genes ?
    • It has been shown that p53 activates transcription of the mir34 family of miRNAs (mir34a–mir34c).
    • miRNAs, bind to cognate sequences in the 3′ untranslated region of mRNAs, preventing translation.
    • Interestingly, blocking mir34 severely hampered the p53 response in cells, while ectopic expression of mir34 without p53 activation is sufficient to induce growth arrest and apoptosis.
    • Thus, mir34 microRNAs are able to recapitulate many of the functions of p53 and are necessary for these functions, demonstrating the importance of mir34 to the p53 response.
    • Targets of mir34s include pro-proliferative genes such as cyclins, and anti-apoptotic genes such as BCL2.
    • p53 regulation of mir34 explains, at least in part, how p53 is able to repress gene expression, and it seems that regulation of this miRNA is crucial for the p53 response
  49. What are the key initiators of the DNA-damage pathway?
    two related protein kinases: ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3 related (ATR)
  50. What are the functions of ATM and ATR once trigerred by DNA damage?
    They phosphorylate a variety of targets, including p53 and DNA-repair proteins. Phosphorylation of these two targets leads to a pause in the cell cycle and stimulation of DNA-repair pathways, respectively
  51. What is the integrative role of P53?
    • Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair, by transcriptional up-regulation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the GADD45 genes.
    • Successful repair of DNA allows cells to proceed with the cell cycle;
    • if DNA repair fails, p53 triggers either apoptosis or senescence.
    • In cells with loss or mutations of p53, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
    • p53 mediates gene repression by activating transcription of miRNAs.
    • p53 activates transcription of the mir34 family of miRNAs. mir34s repress translation of both proliferative genes, such as cyclins, and anti-apoptotic genes, such as BCL2. Repression of these genes can promote either quiescence or senescence as well as apoptosis
  52. p53-mediated ................. may be considered the primordial response to DNA damage
    cell cycle arrest
  53. What are the features of p53-mediated cell cycle arrest?
    • may be considered the primordial response to DNA damage.
    • It occurs late in the G1 phase and is caused mainly by p53-dependent transcription of the CDK inhibitor CDKN1A (p21).
    • p21 inhibits cyclin-CDK complexes and phosphorylation of RB, thereby preventing cells from entering G1 phase.
    • It gives the cells “breathing time” to repair DNA damage.
    • p53 also helps the process by inducing certain proteins, such as GADD45 (growth arrest and DNA damage), that help in DNA repair.
    • p53 can stimulate DNA-repair pathways by transcription-independent mechanisms as well.
    • If DNA damage is repaired successfully, p53 up-regulates transcription of MDM2, leading to its own destruction and thus releasing the cell cycle block.
    • If the damage cannot be repaired, the cell may enter p53-induced senescence or undergo p53-directed apoptosis
  54. What are the features of p53-induced senescence?
    • p53-induced senescence is a permanent cell cycle arrest characterized by specific changes in morphology and gene expression that differentiate it from quiescence or reversible cell cycle arrest.
    • Senescence requires activation of p53 and/or RB and expression of their mediators, such as the CDK inhibitors, and is generally irreversible, although it may require the continued expression of p53.
    • The mechanisms of senescence are unclear but involve epigenetic changes that result in the formation of heterochromatin at different loci throughout the genome.
    • These senescence-associated heterochromatin foci include pro-proliferative genes regulated by E2F; this drastically and permanently alters expression of these E2F targets.
    • Like all p53 responses, senescence may be stimulated in response to a variety of stresses, such as unopposed oncogene signaling, hypoxia, and shortened telomeres
  55. What are the features of p53-induced apoptosis?
    • p53-induced apoptosis of cells with irreversible DNA damage is the ultimate protective mechanism against neoplastic transformation.
    • p53 directs the transcription of several pro-apoptotic genes such as BAX and PUMA.
    • It appears that the affinity of p53 for the promoters and enhancers of DNA-repair genes is stronger than its affinity for pro-apoptotic genes.
    • Thus, the DNA-repair pathway is stimulated first, while p53 continues to accumulate
    • Eventually, if the DNA damage is not repaired, enough p53 accumulates to stimulate transcription of the pro-apoptotic genes and the cell dies.
  56. Summarize the role of P53 in prevention of cancer?
    • p53 links cell damage with DNA repair, cell cycle arrest, and apoptosis.
    • In response to DNA damage, p53 is phosphorylated by genes that sense the damage and are involved in DNA repair.
    • p53 assists in DNA repair by causing G1 arrest and inducing DNA-repair genes.
    • A cell with damaged DNA that cannot be repaired is directed by p53 to undergo apoptosis.
    • With loss of function of p53, DNA damage goes unrepaired, mutations accumulate in dividing cells, and the cell marches along a one-way street leading to malignant transformation
  57. What are the important practical therapeutic implications of P53?
    • Irradiation and chemotherapy, the two common modalities of cancer treatment, mediate their effects by inducing DNA damage and subsequent apoptosis.
    • Tumors that retain normal p53 are more likely to respond to such therapy than tumors that carry mutated alleles of the gene. Such is the case with testicular teratocarcinomas and childhood acute lymphoblastic leukemias.
    • By contrast, tumors such as lung cancers and colorectal cancers, which frequently carry p53 mutations, are relatively resistant to chemotherapy and irradiation
  58. What is the changes in P53/63/73 in basal breast cancers?
    These tumors have been shown to have mutations in p53 and additionally express a dominant-negative version of p63 that antagonizes the apoptotic activity of p73
  59. What is the clinical importance of APC?
    • A class of tumor suppressors whose main function is to down-regulate growth-promoting signals.
    • Germ-line mutations at the APC(5q21) loci are associated with FAP 
    • Both copies of the APC gene must be lost for a tumor to arise. 
    • 70% to 80% of nonfamilial colorectal carcinomas and sporadic adenomas also show homozygous loss of the APC gene, thus firmly implicating APC loss in the pathogenesis of colonic tumors
  60. What are the functions of Wnt signaling pathway?
    • APC is a component of the WNT signaling pathway, which has a major role in controlling cell fate, adhesion, and cell polarity during embryonic development.
    • WNT signaling is also required for self-renewal of hematopoietic stem cells.
    • WNT signals through a family of cell surface receptors called frizzled (FRZ), and stimulates several pathways, the central one involving β-catenin and APC
    • APC and β-catenin are components of the WNT signaling pathway.
    • In resting cells (not exposed to WNT), β-catenin forms a macromolecular complex containing the APC protein. This complex leads to the destruction of β-catenin, and intracellular levels of β-catenin are low. 
    • B, When cells are stimulated by WNT molecules, the destruction complex is deactivated, β-catenin degradation does not occur, and cytoplasmic levels increase. β-catenin translocates to the nucleus, where it binds to TCF, a transcription factor that activates genes involved in cell cycle progression. 
    • C, When APC is mutated or absent, the destruction of β-catenin cannot occur. β-catenin translocates to the nucleus and coactivates genes that promote entry into the cell cycle, and cells behave as if they are under constant stimulation by the WNT pathway.
  61. What happens in the absence of Wnt signaling?
    • An important function of the APC protein is to down-regulate β-catenin. In the absence of WNT signaling APC causes degradation of β-catenin, preventing its accumulation in the cytoplasm
    • It does so by forming a macromolecular complex with β-catenin, axin, and GSK3β, which leads to the phosphorylation and eventually ubiquitination of β-catenin and destruction by the proteasome.

  62. What happens in the presence of WNT?
    • Signaling by WNT blocks the APC-AXIN-GSK3β destruction complex, allowing β-catenin to translocate from the cytoplasm to the nucleus.
    • In the cell nucleus, β-catenin forms a complex with TCF, a transcription factor that up-regulates cellular proliferation by increasing the transcription of c-MYC, cyclin D1, and other genes
  63. True or false: cells with loss of APC behave as if they are under continuous WNT signaling
    True
  64. Colon tumors that have normal APC genes harbor mutations in .................................
    β-catenin that prevent its destruction by APC
  65. Which tumors are characterized by beta catenin pathway mutation?
    • CRC
    •  50% of hepatoblastomas and in approximately 20% of hepatocellular carcinomas
  66. What is the relation of beta catenin to E cadherin?
    • β-catenin binds to the cytoplasmic tail of E-cadherin, a cell surface protein that maintains intercellular adhesiveness.
    • Loss of cell-cell contact, such as in a wound or injury to the epithelium, disrupts the interaction between E-cadherin and β-catenin, and allows β-catenin to travel to the nucleus and stimulate proliferation; this is an appropriate response to injury that can help repair the wound.
    • Re-establishment of these E-cadherin contacts as the wound heals leads to β-catenin again being sequestered at the membrane and reduction in the proliferative signal; these cells are said to be “contact-inhibited.”
  67. Loss of contact inhibition, by mutation of the ..........................occur in carcinomas
    E-cadherin/β-catenin axis
  68. E Cadherin is changed in which tumors?
    • loss of cadherins can favor the malignant phenotype by allowing easy disaggregation of cells, which can then invade locally or metastasize.
    • Reduced cell surface expression of E-cadherin has been noted in many types of cancers, including those that arise in the esophagus, colon, breast, ovary, and prostate.
    • Germline mutations of the E-cadherin gene can predispose to familial gastric carcinoma, and mutation of the gene and decreased E-cadherin expression are present in a variable proportion of gastric cancers of the diffuse type. 
  69. What are the mechanisms of change in E Cadherin in tumors?
    • In a small proportion of cases, there are mutations in the E-cadherin gene (located on 16q);
    • in other cancers, E-cadherin expression is reduced as a secondary effect of mutations in β-catenin genes.
    • Additionally, E-cadherin may be down-regulated by transcription repressors, such as SNAIL, which have been implicated in epithelial-to-mesenchymal transition and metastasis
  70. The location of tumor suppressor genes are suspected by the detection of consistent sites of ..................................................................
    chromosomal deletions or by analysis of LOH.
  71. What is the function of INK4a/ARF locus (CDKN2A)
    • 1) encodes two protein products; the p16/INK4a CDKI, which blocks cyclin D/CDK2-mediated phosphorylation of RB, keeping the RB checkpoint in place.
    • 2) The second gene product, p14/ARF, activates the p53 pathway by inhibiting MDM2 and preventing destruction of p53.
    • 3) Both protein products function as tumor suppressors, and thus mutation or silencing of this locus impacts both the RB and p53 pathways.
    • 4) p16 in particular is crucial for the induction of senescence
  72. What is the mc mutated tumor suppressor in pancreatic adenocarcinoma?
    P16
  73. P16 is mutated or involved in........................................
    Pancreatic cancers, melanoma, bladder, head and neck tumors, ALL, cholangiocarcinomas
  74. In cervical cancer, p16/INK4a is frequently silenced by ...................................
    hypermethylation of the gene, without the presence of a mutation
  75. What is the normal function of TGF-beta?
    • In most normal epithelial, endothelial, and hematopoietic cells, TGF-β is a potent inhibitor of proliferation.
    • It regulates cellular processes by binding to a serine-threonine kinase complex composed of TGF-β receptors I and II.
    • Dimerization of the receptor upon ligand binding leads to activation of the kinase and phosphorylation of receptor SMADs (R-SMADs).
    • Upon phosphorylation, R-SMADs can enter the nucleus, bind to SMAD-4, and activate transcription of genes, including the CDKIs p21 and p15/INK4b.
    • In addition, TGF-β signaling leads to repression of c-MYC, CDK2, CDK4, and cyclins A and E.
    • These changes result in decreased phosphorylation of RB and cell cycle arrest
  76. TGF-beta mutation is seen in what tumors?
    • Mutations affecting the type II receptor are seen in cancers of the colon, stomach, and endometrium.
    • Mutational inactivation of SMAD4 is common in pancreatic cancers
    • In 100% of pancreatic cancers and 83% of colon cancers, at least one component of the TGF-β pathway is mutated
  77. What is the implication of this that in many cancers, loss of TGF-β-mediated growth inhibition occurs at a level downstream of the core signaling pathway, for example, loss of p21 and/or persistent expression of c-Myc?
    These tumor cells can then use other elements of the TGFβ–induced program, including immune system suppression/evasion or promotion of angiogenesis, to facilitate tumor progression
  78. ................................in probably the most common pathway changed in human cancer
    PI3K/AKT signaling
  79. What is the function of PTEN?
    • PTEN is a membrane-associated phosphatase encoded by a gene on chromosome 10q23 .
    • PTEN acts as a tumor suppressor by serving as a brake on the pro-survival/pro-growth PI3K/AKT pathway. This pathway is normally stimulated (along with the RAS and JAK/STAT pathways) when ligands bind to receptor tyrosine kinases and involves a cascade of phosphorylation events.
    • First, PI3K (phosphoinositide 3-kinase) phosphorylates the lipid inositide-3-phosphate to give rise to inositide-3,4,5-triphosphate, which binds and activates the kinase PDK1.
    • PDK1 and other factors in turn phosphorylate and activate the serine/threonine kinase AKT, which is a major node in the pathway with several important functions.
    • By phosphorylating a number of substrates, including BAD and MDM2, AKT enhances cell survival.
    • AKT also inactivates the TSC1/TSC2 complex.
    • Inactivation of TSC1/TSC2 unleashes the activity of yet another kinase called mTOR (mammalian target of rapamycin, a potent immunosuppressive drug), which stimulates the uptake of nutrients such as glucose and amino acids that are needed for growth and augments the activity of several factors that are required for protein synthesis
  80. What is the syndrome associated with PTEN mutation?
    Cowden syndrome, an AD disorder marked by frequent benign growths, such as tumors of the skin appendages, and an increased incidence of epithelial cancers, particularly of the breast, endometrium, and thyroid
  81. Describe the PI3k-Akt pathway?
    • This pathway is normally stimulated when ligands bind to receptor tyrosine kinases and involves a cascade of phosphorylation events.
    • First, PI3K (phosphoinositide 3-kinase) phosphorylates the lipid inositide-3-phosphate to give rise to inositide-3,4,5-triphosphate, which binds and activates the kinase PDK1.
    • PDK1 and other factors in turn phosphorylate and activate the serine/threonine kinase AKT, which is a major node in the pathway with several important functions.
    • By phosphorylating a number of substrates, including BAD and MDM2, AKT enhances cell survival. AKT also inactivates the TSC1/TSC2 complex
  82. What is the function of AKT?
    • By phosphorylating BAD and MDM2, it enhances cell survival.
    • AKT also inactivates the TSC1/TSC2 complex
  83. What is the function of NF1?
    • Neurofibromin, the protein product of the NF1 gene, contains a GTPase-activating domain, which regulates signal transduction through RAS proteins.
    • RAS transmits growth-promoting signals and flips back and forth between GDP-binding (inactive) and GTP-binding (active) states.
    • Neurofibromin facilitates conversion of RAS from an active to an inactive state.
    • With loss of neurofibromin function, RAS is trapped in an active, signal-emitting state
  84. Somatic mutations affecting both alleles of NF2 have been found in ...........................................
    sporadic meningiomas and ependymomas
  85. What is the function of NF2?
    • The product of the NF2 gene, called neurofibromin 2 or merlin.
    • Cells lacking this protein are not capable of establishing stable cell-to-cell junctions and are insensitive to normal growth arrest signals generated by cell-to-cell contact.
  86. Germline mutations of the von Hippel-Lindau (VHL) gene on chromosome 3p are associated with ..............................................................................................
    hereditary RCC, pheochromocytomas, hemangioblastomas of the CNS, retinal angiomas, and renal cysts
  87. Mutations of the VHL gene have also been noted in sporadic ....................
    RCC
  88. What is the function of VHL?
    • The VHL protein is part of a ubiquitin ligase complex. A critical substrate for this activity is HIF1α (hypoxia-inducible transcription factor 1α). In the presence of oxygen, HIF1α is hydroxylated and binds to the VHL protein, leading to ubiquitination and proteasomal degradation.
    • This hydroxylation reaction requires oxygen; in hypoxic environments the reaction cannot occur, and HIF1α escapes recognition by VHL and subsequent degradation.
    • HIF1α can then translocate to the nucleus and turn on many genes, such as the growth/angiogenic factors vascular endothelial growth factor (VEGF) and PDGF. Lack of VHL activity prevents ubiquitination and degradation of HIF1α and is associated with increased levels of angiogenic growth factors
  89. What gene is inactivated in familial or sporadic childhood Wilm's tumor?
    WT (on 11)
  90. What is the function of WT1?
    • The WT1 protein is a transcriptional activator of genes involved in renal and gonadal differentiation.
    • It regulates the mesenchymal-to-epithelial transition that occurs in kidney development.
    • The tumorigenic effect of WT1 deficiency is intimately connected with the role of the gene in the differentiation of genitourinary tissues.
    • Interestingly, although WT1 is a tumor suppressor in Wilms' tumor, a variety of adult cancers, including leukemias and breast carcinomas, have also been shown to overexpress WT1. Since these tissues do not normally express WT1 at all, it has been suggested that WT1 may function as an oncogene in these cancers.
    • Another Wilms' gene, WT2, located on 11p15, is associated with the Beckwith-Wiedemann syndrome 
  91. What is the function of PTCH (patched )gene?
    • PTCH1 and PTCH2 are tumor suppressor genes that encode a cell membrane protein (PATCHED), which functions as a receptor for a family of proteins called Hedgehog.
    • The Hedgehog/PATCHED pathway regulates several genes, including TGF-β and PDGFRA and PDGFRB.
    • Mutations in PTCH are related to Gorlin syndrome, an inherited condition also known as nevoid basal cell carcinoma syndrome
    • PTCH mutations are present in 20% to 50% of sporadic cases of basal cell carcinoma. About one half of such mutations are of the type caused by UV exposure
  92. What are the steps in the process of apoptosis?
    • The process of apoptosis may be divided into an initiation phase, during which some caspases become catalytically active, and an execution phase, during which other caspases trigger the degradation of critical cellular components
    • Initiation of apoptosis occurs principally by signals from two distinct pathways: the intrinsic, or mitochondrial, pathway, and the extrinsic, or death receptor–initiated, pathway

  93. The ....................pathway is the major mechanism of apoptosis in all mammalian cells
    mitochondrial
  94. What are the changes in intrinsic pathway?
    • This pathway of apoptosis is the result of increased mitochondrial permeability and release of pro-apoptotic molecules (death inducers) into the cytoplasm.
    • Mitochondria are remarkable organelles in that they contain proteins such as cytochrome c that are essential for life, but some of the same proteins, when released into the cytoplasm (an indication that the cell is not healthy), initiate the suicide program of apoptosis.
    • The release of these mitochondrial proteins is controlled by a finely orchestrated balance between pro- and anti-apoptotic members of the Bcl family of proteins
    • Growth factors and other survival signals stimulate production of anti-apoptotic proteins, the main ones being Bcl-2, Bcl-x, and Mcl-1. These proteins normally reside in the cytoplasm and in mitochondrial membranes, where they control mitochondrial permeability and prevent leakage of mitochondrial proteins that have the ability to trigger cell death.
    • When cells are deprived of survival signals or their DNA is damaged, or misfolded proteins induce ER stress, sensors of damage or stress are activated.
    • These sensors include Bim, Bid, and Bad which are called “BH3-only proteins.”
    • The sensors in turn activate two critical (proapoptotic) effectors, Bax and Bak, which form oligomers that insert into the mitochondrial membrane and create channels that allow proteins from the inner mitochondrial membrane to leak out into the cytoplasm.
    • BH3-only proteins may also bind to and block the function of Bcl-2 and Bcl-x.
    • At the same time, the synthesis of Bcl-2 and Bcl-x may decline.
    • The net result of Bax-Bak activation coupled with loss of the protective functions of the anti-apoptotic Bcl family members is the release into the cytoplasm of several mitochondrial proteins that can activate the caspase cascade
    • One of these proteins is cytochrome c. Once released into the cytosol, cytochrome c binds to a protein called Apaf-1 (apoptosis-activating factor-1), which forms a wheel-like hexamer that has been called the apoptosome.
    • This complex is able to bind caspase-9, the critical initiator caspase of the mitochondrial pathway, and the enzyme cleaves adjacent caspase-9 molecules, thus setting up an auto-amplification process.
    • Other mitochondrial proteins, with arcane names like Smac/DIABLO, enter the cytoplasm, where they bind to and neutralize cytoplasmic proteins that function as physiologic inhibitors of apoptosis (called IAPs). The normal function of the IAPs is to block the activation of caspases, including executioners like caspase-3, and keep cells alive.
  95. What happens in the The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis?
    • This pathway is initiated by engagement of plasma membrane death receptors on a variety of cells.
    • Death receptors are members of the TNF receptor family that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain because it is essential for delivering apoptotic signals. (Some TNF receptor family members do not contain cytoplasmic death domains; their function is to activate inflammatory cascades 
    • The best-known death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95).
    • FasL is expressed on T cells that recognize self antigens (and functions to eliminate self-reactive lymphocytes), and on some cytotoxic T lymphocytes (which kill virus-infected and tumor cells). When FasL binds to Fas, three or more molecules of Fas are brought together, and their cytoplasmic death domains form a binding site for an adapter protein that also contains a death domain and is called FADD (Fas-associated death domain).
    • FADD that is attached to the death receptors in turn binds an inactive form of caspase-8 (and, in humans, caspase-10), again via a death domain
    • Multiple pro-caspase-8 molecules are thus brought into proximity, and they cleave one another to generate active caspase-8.
    • The enzyme then triggers a cascade of caspase activation by cleaving and thereby activating other pro-caspases, and the active enzymes mediate the execution phase of apoptosis .
    • This pathway of apoptosis can be inhibited by a protein called FLIP, which binds to pro-caspase-8 but cannot cleave and activate the caspase because it lacks a protease domain.
  96. What happens in the The Execution Phase of Apoptosis?
    • The two initiating pathways converge to a cascade of caspase activation, which mediates the final phase of apoptosis.
    • The mitochondrial pathway leads to activation of the initiator caspase-9, and the death receptor pathway to the initiators caspase-8 and -10.
    • After an initiator caspase is cleaved to generate its active form, the enzymatic death program is set in motion by rapid and sequential activation of the executioner caspases.
    • Executioner caspases, such as caspase-3 and -6, act on many cellular components.
    • For instance, these caspases, once activated, cleave an inhibitor of a cytoplasmic DNase and thus make the DNase enzymatically active; this enzyme induces the characteristic cleavage of DNA into nucleosome-sized pieces
    • Caspases also degrade structural components of the nuclear matrix, and thus promote fragmentation of nuclei.
  97. Describe the whole pathway of apoptosis
    • the sequence of events that lead to apoptosis by signaling through the death receptor CD95/Fas (extrinsic pathway) and by DNA damage (intrinsic pathway).
    • The extrinsic pathway is initiated when CD95/Fas binds to its ligand, CD95L/FasL, leading to trimerization of the receptor and its cytoplasmic death domains, which attract the intracellular adaptor protein FADD. This protein recruits procaspase 8 to form the death-inducing signaling complex. Procaspase 8 is activated by cleavage into smaller subunits, generating caspase 8. Caspase 8 then activates downstream caspases such as caspase 3, a typical executioner caspase that cleaves DNA and other substrates to cause cell death. Additionally, caspase 8 can cleave and activate the BH3-only protein BID, activating the intrinsic pathway as well.
    • The intrinsic pathway of apoptosis is triggered by a variety of stimuli, including withdrawal of survival factors, stress, and injury. Activation of this pathway leads to permeabilization of the mitochondrial outer membrane, with resultant release of molecules, such as cytochrome c, that initiate apoptosis. The integrity of the mitochondrial outer membrane is regulated by pro-apoptotic and anti-apoptotic members of the BCL2 family of proteins. The pro-apoptotic proteins 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. A third set of proteins (so-called BH3-only proteins), including BAD, BID, and PUMA, regulate the balance between the pro- and anti-apoptotic members of the BCL2 family. The BH3-only proteins sense death-inducing stimuli and 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/BCL-XL protein barrier, BAX and BAK are activated and form pores in the mitochondrial membrane. Cytochrome c leaks into the cytosol, where it binds to APAF1, activating caspase 9. Like caspase 8 of the extrinsic pathway, caspase 9 can cleave and activate the executioner caspases.
    • The caspases can be inhibited by a family of proteins called Inhibitors of Apoptosis Proteins (IAPs).
  98. How can tumors evade apoptosis?
    • Upregulating IAPs
    • Reduced levels of CD95/Fas may render the tumor cells less susceptible to apoptosis by CD95L/FasL.
    • Some tumors have high levels of FLIP, a protein that can bind death-inducing signaling complex and prevent activation of caspase 8
    • P53 mutation
    • B-cell lymphomas of the follicular type carry a characteristic t(14;18)(q32;q21) translocation. Juxtaposition of IgH (14) with BCL2 (located at 18q21) causes overexpression of the BCL2 protein. This 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 from reduced cell death rather than explosive cell proliferation, they tend to be indolent (slow growing) compared with many other lymphomas

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