Pathology (neoplasia 3/molecular basis)

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  1. What are the principals of molecular carcinogenesis?
    • Nonlethal genetic damage lies at the heart of carcinogenesis
    • A tumor is formed by the clonal expansion of a single precursor cell that has incurred genetic damage (i.e., tumors are monoclonal)
    • Four classes of normal regulatory genes—the growth-promoting proto-oncogenes, the growth-inhibiting tumor suppressor genes, genes that regulate programmed cell death (apoptosis), and genes involved in DNA repair—are the principal targets of genetic damage
    • Carcinogenesis is a multistep process at both the phenotypic and the genetic levels, resulting from the accumulation of multiple mutations
  2. How can clonality of tumors be assessed?
    • Clonality of tumors can be assessed in women who are heterozygous for polymorphic X-linked markers, such as the androgen receptor.
    • The most commonly used method to determine tumor clonality involves the analysis of methylation patterns adjacent to the highly polymorphic locus of the human androgen receptor gene, AR.
    • The frequency of such polymorphisms in the general population is more than 90%, so it is easy to establish clonality by showing that all the cells in a tumor express the same allele.
    • For tumors with acquired cytogenetic aberrations of any type (e.g., a translocation) their presence can be taken as evidence that the proliferation is clonal.
    • Immunoglobulin receptor and T-cell receptor gene rearrangements serve as markers of clonality in B- and T-cell lymphomas, respectively
  3. Image Upload
    Because of random X inactivation, all females are mosaics with two cell populations (with different alleles for the androgen receptor labeled A and B in this case). When neoplasms that arise in women who are heterozygous for X-linked markers are analyzed, they are made up of cells that contain the active maternal (XA) or the paternal (XB) X chromosome but not both
  4. The most commonly used method to determine tumor clonality involves ...........................................................
    the analysis of methylation patterns adjacent to the highly polymorphic locus of the human androgen receptor gene, AR
  5. What is the dominance pattern of proto-oncogene and tumor suppressor genes?
    • Mutant alleles of proto-oncogenes are considered dominant, because they transform cells despite the presence of a normal counterpart.
    • In contrast, typically, both normal alleles of the tumor suppressor genes must be damaged before transformation can occur. However, there are exceptions to this rule; sometimes, loss of a single allele of a tumor suppressor gene reduces levels or activity of the protein enough that the brakes on cell proliferation and survival are released.
    • Loss of gene function caused by damage to a single allele is called haploinsufficiency. Such a finding indicates that dosage of the gene is important, and that two copies are required for normal function
  6. True or False: Genes that regulate apoptosis may behave as proto-oncogenes or tumor suppressor genes.
  7. True or False: Mutations of DNA repair genes directly transform cells by affecting proliferation or apoptosis
  8. How do Mutations of DNA repair genes affect cancer risk?
    • Mutations of DNA repair genes do not directly transform cells by affecting proliferation or apoptosis.
    • Instead, DNA-repair genes affect cell proliferation or survival indirectly by influencing the ability of the organism to repair nonlethal damage in other genes, including proto-oncogenes, tumor suppressor genes, and genes that regulate apoptosis.
    • A disability in the DNA-repair genes can predispose cells to widespread mutations in the genome and thus to neoplastic transformation.
    • Cells with mutations in DNA repair genes are said to have developed a mutator phenotype
  9. What is the role of miRNA in tumorogenesis?
    • act as either oncogenes or tumor suppressors.
    • They do so by affecting the translation of other genes
  10. What is tumor progression?
    • it is well established that over a period of time many tumors become more aggressive and acquire greater malignant potential.
    • This phenomenon is referred to as tumor progression and is not simply a function of an increase in tumor size.
    • increasing malignancy is often acquired in an incremental fashion. At the molecular level, tumor progression and associated heterogeneity most likely result from multiple mutations that accumulate independently in different cells, generating subclones with varying abilities to grow, invade, metastasize, and resist (or respond to) therapy.
    • Some of the mutations may be lethal; others may spur cell growth by affecting additional proto-oncogenes or tumor suppressor genes
    • Even though most malignant tumors are monoclonal in origin, by the time they become clinically evident their constituent cells are extremely heterogeneous.
    • During progression, tumor cells are subjected to immune and nonimmune selection pressures. 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
  11. True or False: Even though most malignant tumors are monoclonal in origin, by the time they become clinically evident their constituent cells are extremely heterogeneous
  12. What are the seven fundamental changes in cell physiology that produce tumors?
    • Self-sufficiency in growth signals
    • Insensitivity to growth-inhibitory signals
    • Evasion of apoptosis
    • Limitless replicative potential
    • Sustained angiogenesis
    • Ability to invade and metastasize
    • Defects in DNA repair
  13. Self-sufficiency in growth signals occurs usually as a consequence of ..................
    oncogene activation
  14. Tumors may be resistant to programmed cell death, as a consequence of .....................................................................................................
    inactivation of p53 or activation of anti-apoptotic genes
  15. What is oncogene-induced senescence?
    mutation of a proto-oncogene drives cells into senescence rather than proliferation
  16. What are oncogenes and protooncogenes?
    • Genes that promote autonomous cell growth in cancer cells are called oncogenes, and their unmutated cellular counterparts are called proto-oncogenes.
    • Oncogenes are characterized by the ability to promote cell growth in the absence of normal growth-promoting signals.
    • Their products, called oncoproteins, resemble the normal products of proto-oncogenes except that oncoproteins are often devoid of important internal regulatory elements, and their production in the transformed cells does not depend on growth factors or other external signals.
    • In this way cell growth becomes autonomous, freed from checkpoints and dependence upon external signals
  17. What is the difference between products of oncogenes and protoncogenes?
    Oncoproteins, resemble the normal products of proto-oncogenes except that oncoproteins are often devoid of important internal regulatory elements, and their production in the transformed cells does not depend on growth factors or other external signals.
  18. What are the physiologic step in cell proliferation?
    • The binding of a growth factor to its specific receptor  
    • 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
    • Transmission of the transduced signal across the cytosol to the nucleus via second messengers or by a cascade of signal transduction molecules  
    • Induction and activation of nuclear regulatory factors that initiate DNA transcription  
    • Entry and progression of the cell into the cell cycle, ultimately resulting in cell division
  19. Proteins encoded by proto-oncogenes may function as ..................................
    • growth factors or their receptors
    • signal transducers
    • transcription factors
    • cell cycle components
  20. What are the GF categories of oncogenes?
    • PDGF-β chain: Overexpression:  Astrocytoma (PDGF-A?)/ Osteosarcoma/ DFSP
    • FGF: Overexpression: Stomach cancer
    • FGF: Amplification Bladder cancer/ Breast cancer/ Melanoma
    • TGFα: Overexpression: Astrocytomas/ Hepatocellular carcinomas
    • HGF: Overexpression: Thyroid cancer
  21. What are some GF receptors serve as oncogenes?
    • EGF-receptor family: ERBB1 (EGFR), ERRB2: Overexpression: Squamous cell carcinoma of lung, glioblastoma
    • FMS-like tyrosine kinase 3: FLT3: Amplification: Breast and ovarian cancers, AML M3
    • Receptor for neurotrophic factors: RET: Point mutation: Leukemia  Point mutation: Multiple endocrine neoplasia 2A and B, familial medullary thyroid carcinomas
    • PDGF receptor: Overexpression, translocation: Gliomas, leukemias, GIST
    • Receptor for stem cell (steel) factor: c-KIT: Point mutation: Gastrointestinal stromal tumors, seminomas, leukemias
    • GTP-binding: KRAS: Point mutation: Colon, lung (late), and pancreatic tumors, serous ovarian cancer (LG)
    • HRAS: Point mutation: Bladder and kidney tumors
    • NRAS: Point mutation: Melanomas, hematologic malignancies
    • Nonreceptor tyrosine kinase: ABL: Translocation: Chronic myeloid leukemia/ Acute lymphoblastic leukemia
    • RAS signal transduction: BRAF: Point mutation: Melanomas, CRC, thyroid
    • WNT signal transduction: β-catenin: Point mutation: Hepatoblastomas/ hepatocellular carcinoma
  23. The ............... is the most frequently altered oncogene in pancreatic cancer.
    KRAS gene (chromosome 12p)
  24. What are the NUCLEAR-REGULATORY PROTEINS involved in cancer in oncogenes?
    • Transcriptional activators
    • C-MYC: Translocation: Burkitt lymphoma
    • N-MYC: Amplification: Neuroblastoma, small-cell carcinoma of lung
    • L-MYC: Amplification: Small-cell carcinoma of lung
  25. What are the cell-cycle related oncogenes?
    • Cyclins
    • Cyclin D: Translocation: Mantle cell lymphoma/ Amplification: Breast and esophageal cancers, oral SCC (late), Aggressive adenomas of hypophysis
    • Cyclin E: Overexpression: Breast cancer
    • Cyclin-dependent kinase
    • CDK4: Amplification or point mutation: Glioblastoma, melanoma, sarcoma
  26. How can GF oncogenes cause oncogenesis?
    • Normal cells require stimulation by growth factors to undergo proliferation. Most soluble growth factors are made by one cell type and act on a neighboring cell to stimulate proliferation (paracrine action).
    • Many cancer cells, however, acquire the ability to synthesize the same growth factors to which they are responsive, generating an autocrine loop
    •  In all likelihood growth factor driven proliferation contributes to the malignant phenotype by increasing the risk of spontaneous or induced mutations in the proliferating cell population
  27. many ................secrete platelet-derived growth factor (PDGF) and express the PDGF receptor, and many .............make both transforming growth factor α (TGF-α) and its receptor
    glioblastomas /sarcomas
  28. True or false: in most instances the growth factor gene itself is not altered or mutated
    • True
    • (More commonly, products of other oncogenes that lie along many signal transduction pathways, such as RAS, cause overexpression of growth factor genes, thus forcing the cells to secrete large amounts of growth factors, such as TGF-α)
  29. How can oncogenesis occur in growth factor receptors that are transmembrane proteins with an external ligand-binding domain and a cytoplasmic tyrosine kinase domain?
    • In the normal forms of these receptors, the kinase is transiently activated by binding of the specific growth factors, followed rapidly by receptor dimerization and tyrosine phosphorylation of several substrates that are a part of the signaling cascade. 
    • The oncogenic versions of these receptors are associated with constitutive dimerization and activation without binding to the growth factor.
    • Hence, the mutant receptors deliver continuous mitogenic signals to the cell, even in the absence of growth factor in the environment
  30. .............................., exemplifies oncogenic conversion via mutations and gene rearrangements
    The RET proto-oncogene, a receptor tyrosine kinase
  31. The RET protein is a receptor for the ............................... and structurally related proteins that promote cell survival during neural development
    glial cell line–derived neurotrophic factor
  32. RET is normally expressed in ......................
    neuroendocrine cells, such as parafollicular C cells of the thyroid, adrenal medulla, and parathyroid cell precursors
  33. How can RET mutations cause carcinogenesis?
    • Point mutations in the RET proto-oncogene are associated with dominantly inherited MEN types 2A and 2B and familial medullary thyroid carcinoma.
    • In MEN-2A, point mutations in the RET extracellular domain cause constitutive dimerization and activation, leading to medullary thyroid carcinomas and adrenal and parathyroid tumors.
    • In MEN-2B, point mutations in the RET cytoplasmic catalytic domain alter the substrate specificity of the tyrosine kinase and lead to thyroid and adrenal tumors without involvement of the parathyroid.
    • In all these familial conditions, the affected individuals inherit the RET mutation in the germline.
    • Sporadic medullary carcinomas of the thyroid are associated with somatic rearrangements of the RET gene, generally similar to those found in MEN-2B.
  34. Point mutations in FLT3, the gene encoding the FMS-like tyrosine kinase 3 receptor, that lead to constitutive signaling have been detected in ...........
    myeloid leukemias
  35. In ..........., the entire cytoplasmic domain of the PDGF receptor is fused with a segment of an ETS family transcription factor, resulting in permanent dimerization of the PDGF receptor
    Chronic myelomonocytic leukemias with the (5;12) translocation
  36. Greater than 90% of gastrointestinal stromal tumors have a constitutively activating mutation in ................................
    the receptor tyrosine kinase c-KIT or PDGFR, which are the receptors for stem cell factor and PDGF, respectively
  37. What is targeted therapy in cancer?
    • Greater than 90% of gastrointestinal stromal tumors have a constitutively activating mutation in the receptor tyrosine kinase c-KIT or PDGFR, which are the receptors for stem cell factor and PDGF, respectively.
    • These mutations are amenable to specific inhibition by the tyrosine kinase inhibitor imatinib mesylate.
    • This type of therapy, directed to a specific alteration in the cancer cell, is called targeted therapy
  38. What is the mc change in GF receptor that lead to carcinogenesis?
    overexpression of normal forms of growth factor receptors
  39. What are the examples of GF receptor overexpression in tumors?
    • The normal form of ERBB1, the EGF receptor gene, is overexpressed in up to 80% of squamous cell carcinomas of the lung, in 50% or more of glioblastomas ( Chapter 28 ), and in 80% to 100% of head and neck tumors.
    • Likewise, the ERBB2 gene (also called HER-2/NEU), the second member of the EGF receptor family, is amplified in approximately 25% of breast cancers and in human adenocarcinomas arising within the ovary, lung, stomach, and salivary glands.
  40. Why new therapeutic agents consisting of monoclonal antibodies specific to ERBB2 can be beneficial in treating cancer?
    Because the molecular alteration in ERBB2 is specific for the cancer cells
  41. ..................................... is the single most common abnormality of proto-oncogenes in human tumors
    Point mutation of RAS family genes
  42. What are the important cancers with Ras mutation?
    • 90% of pancreatic adenocarcinomas and cholangiocarcinomas
    • 50% of colon, endometrial, and thyroid cancers
    • 30% of lung adenocarcinomas and myeloid leukemias
  43. What are the types of Ras mutation in different cancers?
    In general, carcinomas (particularly from colon and pancreas) have mutations of KRAS, bladder tumors have HRAS mutations, and hematopoietic tumors bear NRAS mutations.
  44. RAS mutations are infrequent in certain other cancers, such as those arising in the .................................
    uterine cervix or breast.
  45. What is the function of Ras?
    • RAS plays an important role in signaling cascades downstream of growth factor receptors, resulting in mitogenesis.
    • For example, abrogation of RAS function blocks the proliferative response to EGF, PDGF, and CSF-1.
    • Normal RAS proteins are tethered to the cytoplasmic aspect of the plasma membrane, as well as the endoplasmic reticulum and Golgi membranes.
    • They can be activated by growth factor binding to receptors at the plasma membrane
  46. How does Ras function?
    • RAS is a member of a family of small G proteins that bind guanosine nucleotides (guanosine triphosphate, GTP and guanosine diphosphate, GDP), similar to the larger trimolecular G proteins.
    • Normally RAS proteins flip back and forth between an excited signal-transmitting state and a quiescent state.
    • In the inactive state, RAS proteins bind GDP.
    • Stimulation of cells by growth factors leads to exchange of GDP for GTP and subsequent conformational changes that generates active RAS.
    • The activated RAS stimulates downstream regulators of proliferation, such as the mitogen-activated protein (MAP) kinase cascade, which floods the nucleus with signals for cell proliferation
    • The orderly cycling of the RAS protein depends on two reactions: (1) nucleotide exchange (GDP by GTP), which activates RAS protein, and (2) GTP hydrolysis, which converts the GTP-bound, active RAS to the GDP-bound, inactive form. Both these processes are extrinsically regulated by other proteins.
    • The removal of GDP and its replacement by GTP during RAS activation are catalyzed by a family of guanine nucleotide–releasing proteins.
    • Conversely, the GTPase activity intrinsic to normal RAS proteins is dramatically accelerated by GTPase-activating proteins (GAPs). Thus, GAPs function as “brakes” that prevent uncontrolled RAS activity
  47. What does mutation alter in Ras protein?
    The affected residues lie within either the GTP-binding pocket or the enzymatic region essential for GTP hydrolysis, and thus markedly reduce the GTPase activity of the RAS protein
  48. Ras oncogene has markedly......... GTPase activity
  49. Mutated RAS is trapped in its ........................., and the cell is forced into a continuously proliferating state
    activated GTP-bound form
  50. How can GAP mutation cause cancer?
    • The consequences of mutations in RAS protein would be mimicked by mutations in the GAPs that fail to activate the GTPase activity and thus restrain normal RAS proteins.
    • Indeed, disabling mutation of neurofibromin 1, a GAP, is associated with the inherited cancer syndrome familial neurofibromatosis type 1
  51. How can Ras signaling pathway be affected by mutations other than Ras?
    • downstream members of the RAS signaling cascade (RAS/RAF/MAP kinase) may also be altered in cancer cells, resulting in a similar phenotype.
    • Thus, mutations in BRAF, one of the members of the RAF family, have been detected in more than 60% of melanomas and in more than 80% of benign nevi.
    • This suggests that dysregulation of the RAS/RAF/MAP kinase pathway may be one of the initiating events in the development of melanomas, although it is not sufficient by itself to cause tumorigenesis
  52. .................mutation has been seen in benign nevi and melanoma
  53. Why does BRAF mutation alone cannot cause melanoma?
    BRAF mutations alone lead to oncogene-induced senescence giving rise to benign nevi rather than malignant melanoma
  54. What should happen that a BRAF mutation could cause a melanoma?
    oncogene-induced senescence is a barrier to carcinogenesis that must be overcome by mutation and disabling of key protective mechanisms, such as those provided by the p53 gene
  55. Mutation in ....................exemplify Mutations that unleash latent oncogenic activity occur in non-receptor-associated tyrosine kinases, which normally function in signal transduction pathways that regulate cell growth
    c-ABL tyrosine kinase
  56. How does BCR-ABL translocation affect tumor behavior?
    • In CML and some ALL, the ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22 , where it fuses with the BCR gene.
    • The resultant chimeric gene encodes a constitutively active, oncogenic BCR-ABL tyrosine kinase.
    • Several structural features of the BCR-ABL fusion protein contribute to the increased kinase activity, but the most important is that the BCR moiety promotes the self-association of BCR-ABL. This is a common theme, since many different oncogenic tyrosine kinases consist of fusion proteins in which the non–tyrosine kinase partner drives self-association.
    • Treatment of CML has been revolutionized by the development of imatinib mesylate, a “designer” drug with low toxicity and high therapeutic efficacy that inhibits the BCR-ABL kinase. Despite accumulation of numerous mutations throughout the genome, signaling through the BCR-ABL gene is required for the tumor to persist, hence inhibition of its activity is effective therapy
    • Image Upload
  57. ............. is an early, perhaps initiating event, during leukemogenesis in CML and ALL
    BCR-ABL translocation
  58. What structural features of the BCR-ABL fusion protein contribute to the increased kinase activity?
    BCR moiety promotes the self-association of BCR-ABL
  59. What are the examples of nonreceptor tyrosine kinases are activated by point mutations that abrogate the function of negative regulatory domains that normally hold enzyme activity in check?
    • For example, several myeloproliferative disorders, particularly polycythemia vera and primary myelofibrosis, are highly associated with activating point mutations in the tyrosine kinase JAK2 
    • The aberrant JAK2 kinase in turn activates transcription factors of the STAT family, which promote the growth factor–independent proliferation and survival of the tumor cells.
    • Recognition of this molecular lesion has led to trials of JAK2 inhibitors in myeloproliferative disorders
  60. What is the importance of Transcription Factors in carcinogenesis?
    • All signal transduction pathways converge to the nucleus, where a large bank of responder genes that orchestrate the cell's orderly advance through the mitotic cycle are activated.
    • Indeed, the ultimate consequence of signaling through oncogenes like RAS or ABL is inappropriate and continuous stimulation of nuclear transcription factors that drive growth-promoting genes.
    • Transcription factors contain specific amino acid sequences or motifs that allow them to bind DNA or to dimerize for DNA binding.
    • Binding of these proteins to specific sequences in the genomic DNA activates transcription of genes.
    • Growth autonomy may thus occur as a consequence of mutations affecting genes that regulate transcription.
    • A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, are transcription factors that regulate the expression of growth-promoting genes, such as cyclins. 
    • Of these, MYC is most commonly involved in human tumors
  61. the most commonly involved TF in human tumors/
  62. The ...................... is expressed in virtually all eukaryotic cells and belongs to the immediate early response genes, which are rapidly induced when quiescent cells receive a signal to divide
    MYC proto-oncogene
  63. What are the activities of MYC?
    • 1) Histone acetylation, reduced cell adhesion, increased cell motility, increased telomerase activity, increased protein synthesis, decreased proteinase activity, and other changes in cellular matbolism that enable a high rate of cell division
    • 2) enhance self-renewal, block differentiation
    • 3) Reprogramming into pluripotent SC
    • 4) selection of origins of replication (mutation--> increased proliferation of DNA)
  64. What happens if MYC activation occurs in the absence of survival signals (growth factors)
    cells in culture undergo apoptosis
  65. True or False: After a transient increase of MYC messenger RNA, the expression declines to a basal level
  66. Dysregulation of MYC expression resulting from translocation of the gene occurs in .........................
    Burkitt lymphoma
  67. N-MYC and L-MYC genes are amplified in .....................and............. respectively
    neuroblastomas /small-cell cancers of the lung,
  68. Image Upload
    Amplification of the N-MYC gene in human neuroblastomas. The N-MYC gene, normally present on chromosome 2p, becomes amplified and is seen either as extra chromosomal double minutes or as a chromosomally integrated, homogeneous staining region (HSR)
  69. What are the roles of cyclines and CDKs?
    • The orderly progression of cells through the various phases of the cell cycle is orchestrated by cyclin-dependent kinases (CDKs), which are activated by binding to cyclins, so called because of the cyclic nature of their production and degradation.
    • The CDK-cyclin complexes phosphorylate crucial target proteins that drive the cell through the cell cycle.
    • On completion of this task, cyclin levels decline rapidly
  70. What are the activity of each cyclin-CDK?
    • Cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 regulate the G1-to-S transition by phosphorylation of the RB protein (pRB).
    • Cyclin A–CDK2 and cyclin A–CDK1 are active in the S phase.
    • Cyclin B–CDK1 is essential for the G2-to-M transition.
    • Two families of CDKIs can block activity of CDKs and progression through the cell cycle. The so-called INK4 inhibitors, composed of p16, p15, 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.
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  71. cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 regulate the .......... transition by phosphorylation of the RB protein (pRB)
  72. Cyclin A–CDK2 and cyclin A–CDK1 are active in the ...........
    S phase
  73. .............. is essential for the G2-to-M transition
    Cyclin B–CDK1
  74. Which CDKI inhibit G1 to S transition?
    INK4 inhibitors, composed of p16, p15, p18, and p19, act on cyclin D–CDK4 and cyclin D–CDK6
  75. What are the functions of CDK1,2,4?
    • CDK4: Forms a complex with cyclin D that phosphorylates RB, allowing the cell to progress through the G1 restriction point.
    • CDK2: Forms a complex with cyclin E in late G1, which is involved in G1/S transition. Forms a complex with cyclin A at the S phase that facilitates G2/M transition.
    • CDK1: Forms a complex with cyclin B that facilitates G2/M transition
  76. Which cyclin/CDK phosphorylate RB?
    CDK4/cyclin D
  77. ......................, allowing the cell to progress through the G1 restriction point
    CDK4 forms a complex with cyclin D that phosphorylates RB
  78. What are the functions of CDKI?
    • CIP/KIP family: p21, p27 (CDKN2A-C): Block the cell cycle by binding to cyclin-CDK complexes; p21 is induced by the tumor suppressor p53; p27 responds to growth suppressors such as TGF-β.
    • INK4/ARF family (CDKN1A-D): p16/INK4a binds to cyclin D–CDK4 and promotes the inhibitory effects of RB; p14/ARF increases p53 levels by inhibiting MDM2 activity
  79. What are the two important checkpoint components?
    • P53
    • AT
  80. p21 is induced by ...........
  81. What are the major functions of P53?
    • Tumor suppressor gene altered in the majority of cancers; causes cell cycle arrest and apoptosis.
    • Acts mainly through p21 to cause cell cycle arrest.
    • Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX.
    • Levels of p53 are negatively regulated by MDM2 through a feedback loop.
    • p53 is required for the G1/S checkpoint and is a main component of the G2/M checkpoint
  82. Levels of p53 are negatively regulated by .............through a feedback loop
  83. What is the role of AT?
    • Activated by mechanisms that sense double-stranded DNA breaks.
    • Transmits signals to arrest the cell cycle after DNA damage.
    • Acts through p53 in the G1/S checkpoint.
    • At the G2/M checkpoint, it acts both through p53-dependent mechanisms and through the inactivation of CDC25 phosphatase, which disrupts the cyclin B–CDK1 complex.
    • Component of a network of genes that include BRCA1 and BRCA2, which link DNA damage with cell cycle arrest and apoptosis
  84. Which gene is a component of a network of genes that include BRCA1 and BRCA2, which link DNA damage with cell cycle arrest and apoptosis
  85. AT act G2/M checkpoint
    • P53
    • CDC25 phosphatase (disrupt cyclin B-CDK1)
  86. Mishaps affecting the expression of cyclin.............or CDK... seem to be a common event in neoplastic transformation
    D/ 4
  87. What are the tumors associated with increased cyclin D?
    • The cyclin D genes are overexpressed in many cancers, including those affecting the breast, esophagus, liver, and a subset of lymphomas.
    • Amplification of the CDK4 gene occurs in melanomas, sarcomas, and glioblastomas
  88. .............................................., inhibits the CDKs broadly
    The CIP/WAF family of CDKIs, composed of three proteins, called p21 (CDKN1A), p27 (CDKN1B), and p57 (CDKN1C)
  89. ..........................., has selective inhibitory effects on cyclin D/CDK4 and cyclin D/CDK6.
    INK4 family of CDKIs, made up of p15 (CDKN2B), p16 (CDKN2A), p18 (CDKN2C), and p19 (CDKN2D)
  90. Mitogenic signals that dampen the activity of a variety of ways, relieve inhibition of cyclin E-CDK2 and thus allowing the cell cycle to proceed
  91. Germline mutation of P16 is seen in...........
  92. What is the relation of P16 to tumors?
    • Germline mutations--> 25% of melanoma-prone kindreds.
    • Somatically acquired deletion or inactivation --> 75% of pancreatic carcinomas, 40% to 70% of glioblastomas, 50% of esophageal cancers, 20% to 70% of acute lymphoblastic leukemias
  93. Somatic mutation in most common in pancreatic cancer
  94. What are the cell cycle checkpoints?
    There are two main cell cycle checkpoints, one at the G1/S transition and the other at G2/M
  95. The........  phase is the point of no return in the cell cycle
  96. What is the importance of G1/S checkpoint?
    • The S phase is the point of no return in the cell cycle.
    • Before a cell makes the final commitment to replicate, the G1/S checkpoint checks for DNA damage; if damage is present, the DNA-repair machinery and mechanisms that arrest the cell cycle are put in motion.
    • The delay in cell cycle progression provides the time needed for DNA repair; if the damage is not repairable, apoptotic pathways are activated to kill the cell.
    • Thus, the G1/S checkpoint prevents the replication of cells that have defects in DNA, which would be perpetuated as mutations or chromosomal breaks in the progeny of the cell.
    • DNA damaged after its replication can still be repaired as long as the chromatids have not separated
  97. What is the function of G2/M checkpoint?
    • The G2/M checkpoint monitors the completion of DNA replication and checks whether the cell can safely initiate mitosis and separate sister chromatids.
    • This checkpoint is particularly important in cells exposed to ionizing radiation. Cells damaged by ionizing radiation activate the G2/M checkpoint and arrest in G2; defects in this checkpoint give rise to chromosomal abnormalities
  98. Cells damaged by ionizing radiation activate the ..... checkpoint and arrest in ....
  99. What are the sensors of DNA damage in cell cycle?
    • The sensors and transducers of DNA damage seem to be similar for the G1/S and G2/M checkpoints.
    • They include, as sensors, proteins of the RAD family and ataxia telangiectasia mutated (ATM) and as transducers, the CHK kinase families.
    • The checkpoint effector molecules differ, depending on the cell cycle stage at which they act.
    • In the G1/S checkpoint, cell cycle arrest is mostly mediated through p53, which induces the cell cycle inhibitor p21.
    • Arrest of the cell cycle by the G2/M checkpoint involves both p53-dependent and p53-independent mechanisms
  100. Defects in ...................... are a major cause of genetic instability in cancer cells
    cell cycle checkpoint components
Card Set:
Pathology (neoplasia 3/molecular basis)
2013-10-15 18:39:24
Pathology neoplasia molecular basis

Pathology (neoplasia 3/molecular basis)
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