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biochemistry > Cancer > Flashcards

Cancer Flashcards

1
Q

Epigenetic changes

A

Any process that alters gene activity without changing DNA sequence and leads to modifications that can be transmitted to cell’s progeny

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2
Q

Proto-oncogenes

A

Genes associated with control of cell division, generally acting to promote cell growth (ex. encode growth factors, growth factor receptors, protein kinases)

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3
Q

Oncogene

A

Mutated form of proto-oncogene that is excessively active in growth promotion (act like stuck accelerator)

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4
Q

Tumor suppressor genes

A

Function to inhibit cell growth and division; mutations that inactivate these allow for inappropriate cell division (act like brake failure)

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5
Q

Caretaker genes

A

Protect integrity of genome (ex. DNA repair enzymes); mutations that inactivate these cause cells to accumulate DNA damage at increased rate

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6
Q

6 acquired capabilities of cancer cells

A
  1. Self-sufficiency in growth signals
  2. Insensitivity to antigrowth signals
  3. Evasion of apoptosis
  4. Limitless replicative potential
  5. Sustained angiogenesis (blood supply)
  6. Tissue invasion and metastasis
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7
Q

Self-sufficiency in growth signals

A

Oncogene products send inappropriate growth signals (mitogens) to stimulate active division

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8
Q

Insensitivity to antigrowth signals

A

Loss of tumor suppressor function leads to loss of sensitivity to antigrowth signal

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9
Q

Evasion of apoptosis

A

Mutations in apoptosis pathway components blocks attrition

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10
Q

Limitless replicative potential

A

Reactivation of telomerase can confer unlimited cell division

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11
Q

Sustained angiogenesis

A

In tumor development, cells achieve ability to promote and sustain angiogenesis, providing a blood supply to tumor

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12
Q

Tissue invasion and metastasis

A

Ability to complete migration of tumor spawn cells that move out and invade nearby tissues (depends on changes in expression of cell surface molecules)

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13
Q

How does the conversion of proto-oncogene to oncogene cause cancer?

A

Conversion preserves activity of the protein but either results in excess protein production or disrupts normal control of the function; gain of function is normally dominant

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14
Q

How can a proto-oncogene be converted to an oncogene?

A
  1. Deletion or point mutation in coding sequence that leads to hyperactive protein made in normal amounts
  2. Regulatory mutation that overproduces normal protein
  3. Gene amplification that overproduces normal protein
  4. Chromosome rearrangement that affects nearby DNA sequence to cause overproduction of normal protein
  5. Chromosome rearrangement that causes fusion to actively transcribed gene which produces hyperactive fusion protein
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15
Q

ErbB1 (HER1)

A

Receptor tyrosine kinase for epidermal growth factor (EGF) that belongs to a small family of related receptors called HER2, HER3, and HER4; receptors function as homo- or heterodimers that are triggered by ligand binding to dimerize, activate kinase domain and autophosphorylate

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16
Q

How can ErbB1 be converted into a functioning oncoprotein?

A

Can be mutated into constitutively active form by a mutation that truncates protein and removes extracellular domain that normally binds EGF, resulting in activation of kinase domain and causing signal to grow to be delivered in absence of stimulus

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17
Q

How can HER2 be converted into a functioning oncoprotein?

A

Can be mutated into constitutively active form by a point mutation in the region of the protein spanning plasma membrane allowing receptor dimerization and autophosphorylation in absence of ligand

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18
Q

How does HER2 contribute to breast cancer?

A

Overexpression of this protein leads to superabundance of receptors, which allows cancer cell to respond to low concentrations of EGF/related hormones and express normal amounts, leading to tumor formation

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19
Q

How can mutant forms of Ras contribute to development of cancer?

A

Mutations leading to constitutively active Ras uncouple Ras activation from binding of growth factor to receptor (GRB2 and Sos not needed to activate Ras and MAP kinase kinase/MAP kinase are constantly active)

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20
Q

What are common Ras mutations?

A

Occur at amino acid positions 12, 13, or 61 (all favor GTP binding and lead to active Ras)

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21
Q

How can mutated forms of c-Fos and c-Myc contribute to development of cancer?

A

Both are transcription factors that play a role in activating genes such as cyclins; when mutated to oncogenic forms, their mRNA and protein become stabilized so that their levels do NOT decrease within a few hours as they should and they cause inappropriate activation of growth-promoting genes downstream

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22
Q

Burkitt’s lymphoma

A

Results from inappropriate Myc activity due to translocation of c-Myc gene from chromosome 8 to 14 where it can be regulated by promoter elements of antibody heavy chains and is therefore continually expressed (occurs in B-cells)

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23
Q

How does a tumor suppressor gene mutation lead to cancer?

A

Damage to both alleles is required to give rise to unregulated cell proliferation (generally recessive); typically a person inherits germline mutation and develops somatic mutation

24
Q

Two-hit model

A

Model of tumorigenesis in which an individual inherits a germline mutation on one allele of a tumor suppressor gene and later develops a somatic mutation in a second allele allowing tumor to progress

25
Q

Two-hit model related to retinoblastoma

A

Hereditary form of retinoblastoma is caused by inheritance of one defective copy of RB1 gene and second somatic mutation in other RB1 gene copy in retinal cell resulting in no functional Rb protein, leading to tumors in both eyes

26
Q

What is the normal function of Rb?

A

Functions to inhibit cell cycle progression by binding to and sequestering E2F proteins

27
Q

Sporadic retinoblastoma

A

Individual inherits two normal RB1 alleles and two separate mutations in retinal cell or progeny produce cell with both copies of RB1 that are non-functional (very rare)

28
Q

p53 in a normal cell situation

A

Instability due to association with Mdm2, an E3 ubiquitin ligase that targets p53 for destruction by proteasome

29
Q

How does p53 trigger cell cycle arrest or apoptosis in response to DNA damage?

A

ATM (or ATR) is activated in response to DNA damage, rendering p53 more stable due to phosphorylation by ATM/ATR that displaces Mdm2; levels of p53 increase in the cell and transcription of genes such as p21CIP1 (causes cell cycle arrest), DNA repair enzymes, and induction of apoptosis if necessary

30
Q

How can a mutation affecting p53 cause cancer?

A

Mutations in TP53 (encodes p53) are most common genetic alterations found in cancers and causes cell to allow DNA damage to go without repair; occurs so commonly because p53 is homotetramer and any TP53 allele with a mutation will reduce p53 activity (dominant negative mutation)

31
Q

Li-Fraumeni syndrome

A

Rare, heritable condition causing greater susceptibility to variety of cancers (causes lots of tumors); arises due to inheritance of mutant TP53 allele that disrupts tetramer function, allowing cells to continuously divide and lead to tumors (dominant inheritance)

32
Q

HPV-induced cervical cancer

A

HPV virus produces proteins E6 and E7 that inhibit p53 (accumulation of DNA damage) and Rb (no inhibition of cell cycle), which is enough to induce cell proliferation without mutations

33
Q

Neurofibromatosis 1

A

Condition that occurs due to loss of function in both alleles of NF1 gene, which encodes neurofibromin, keeping downstream products of Ras activated longer; causes neurofibromas (tumors of nerve sheath cells) to form – follows two-hit model

34
Q

What is the normal function of neurofibromin?

A

Accelerates rate of Ras hydrolyzation of GTP to return to inactive form, turning off downstream phosphorylation

35
Q

BRCA1 and BRCA2 genes

A

Caretaker genes that are important for double-stranded DNA break repair that are involved in homologous recombination (both) and G1/S and G2/M checkpoints (BRCA1 only); deliver effector proteins to sites of double-stranded DNA breaks

36
Q

How does hereditary breast and ovarian cancer (HBOC) syndrome occur?

A

Autosomal dominant inheritance; loss/mutation of BRCA1 or BRCA2 genes in one allele in germline that lead to cancer with loss of second allele; accumulation of mutations occurs due to inability to properly fix double-stranded DNA breaks

37
Q

How can epigenetic changes contribute to development of cancers?

A
  • -DNA mismatch repair can become defective due to loss of function of genes required to encode key protein for process due to methylation (leading to transcriptional silencing)
  • -Loss of methylation can lead to transcriptional activation and overproduction of gene product that is growth-promoting
  • -Epigenetic changes = about as common as mutational changes
38
Q

Breakage/fusion/bridge cycles due to damage to checkpoint mechanisms

A

Shortened chromosomes lacking telomere sequences can initiate breakage/fusion/bridge cycles; these lead to chromosome instability and generation of two centromeres, which break to result in one copy with terminal deletion and one with inverted repeat – leads to mitotic catastrophe and cell dies

39
Q

How does telomerase re-expression cause cancer?

A

Tumor cells re-express/up-regulate telomerase to interrupt breakage/fusion/bridge cycles and allow cell survival

40
Q

HIF-1αβ

A

Oxygen-sensitive transcription factor stimulated by hypoxia

41
Q

How is HIF-1α regulated under conditions of normoxia?

A

It gets hydroxylated by proline hydroxylase, recruiting an E3 ubiquitin ligase that targets it for destruction

42
Q

How is HIF-1α regulated under conditions of hypoxia?

A

Due to lack of oxygen, HIF-1α escapes degradation and pairs with HIF-1β to form HIF-1αβ to promote angiogenesis by activating transcription of genes such as vascular endothelial growth factor (VEGF)

43
Q

Process of epithelial cell tumor metastasis

A
  1. E-cadherin molecule interactions break down, freeing cells from primary tumor (normally keep cells tight together)
  2. Tumor cells secrete enzymes like matrix metalloproteases that break down basement membrane
  3. Degradation of basement membrane components like collagen IV and laminin generates signals interacting with cell surface receptors to stimulate migration
  4. Vascular basement membrane is degraded and intravasation occurs (tumor cells entering cirulation)
  5. Cells that are not degraded by immune system exit bloodstream through extravasation
44
Q

Familial adenomatous polyposis (FAP)

A

Causes development of polyps in colon due to mutation in APC gene encoding tumor suppressor gene APC (down-regulates growth promoting signals that come through WNT pathway)

45
Q

What is the role of APC in WNT signaling pathway and how can loss of its function lead to cell proliferation?

A
  • -Signal regulated by APC comes through WNT pathway
  • -In absence of WNT, β-catenin forms macromolecular “destruction complex” with APC and other proteins, resulting in phophorylation, ubiquitination, and destruction of β-catenin by proteasome
  • -When WNT is present, “destruction complex” is not formed; β-catenin is not destroyed and translocates to nucleus where it increases transcription of genes including Myc and cyclin D
  • -APC is also part of protein machinery attaching microtubules to kinetochore of chromosomes during motisis (loss can lead to aneuploidy and genomic mutations)
46
Q

Formation of adenomatous polyps in FAP

A

FAP patients are born with one defective APC allele and eventually the second allele loses function – leads to development of adenomatous polyps cells which are driven to proliferate in unregulated manner and accumulate additional mutations (often Ras and TP53)

47
Q

Development of carcinoma in FAP

A

More mutations occur, leading to gross chromosomal changes and increased telomerase – eventually can move out of tumor and migrate to new sites, forming new tumor

48
Q

HNPCC (Lynch syndrome)

A

Familial carcinomas of the colon but also others; result in defects of DNA mismatch repair; MSH2 or MLH1 are main genes impacted; use two-hit model; mutations accumulate in microsatellite repeats and lead to microsatellite instability

49
Q

Bax

A

Pro-apoptotic protein with a DNA sequence including microsatellite repeats; mutations in gene reducing its function can allow survival of genetically-abnormal cells that would normally die by apoptosis

50
Q

Translocation for Philadelphia chromosome

A

Occurs between chromosomes 9 and 22

51
Q

What cancer is the Philadelphia chromosome characteristic of?

A

Chronic myeloid leukemia

52
Q

What gene fusion is generated by creation of Philadelphia chromosome?

A

BCR (function unclear) and ABL1 (soluble protein tyrosine kinase found in cytoplasm or nucleus) – produces hybrid Bcr-Abl tyrosine kinase that is constitutively active and can phosphorylate (can trigger expansion in WBCs if occurring in bone marrow)

53
Q

Imatinib mesylate

A

Drug designed by rational drug design to inhibit Bcr-Abl; can be effective but can develop resistance

54
Q

What are more potent Bcr-Abl inhibitors?

A

Nilotinib and dasatinib

55
Q

Trastuzumab

A

Monoclonal antibody that binds to extracellular domain of HER2 with potent anti-tumor effects

biochemistry (14 decks)

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