Molecular Mechanisms of Cancer Flashcards
(91 cards)
1
Q
Trophic factor of primary cells
A
“Bad” - if trophic factor is removed - cell undergoes apoptosis
2
Q
Cyclin and CDK control of cell division
A
3
Q
E2F transcription factor
A
4
Q
The cell cycle can be arrested due to DNA damage in what stage(s) of the cell cycle?
A
G1 and G2
5
Q
Maintenance methylase
A
Ensures that the daughter DNA strand has the same methylation pattern as parent strand - so that same genes will be expressed in daughter cell
6
Q
Burkitt’s lymphoma
A
7
Q
How do transforming retroviruses produce cancers?
A
By carrying extraviral DNA that encodes and oncogene
8
Q
How do DNA viruses cause transformation?
A
They are sometimes, accidentally, incorporated into the host cell genome
9
Q
List common tumor supressor genes
A
10
Q
Tumor supressor gene that functions as a transcription factor
A
p53
11
Q
Series of mutations associated with colon cancer
A
- Loss of APC
- Activation of K-ras
- Loss of DCC
- Loss of p53
12
Q
Function of Mdm2
A
Prevents p53 activity in the absencce of DNA damage
13
Q
The majority of mutations in p53 are located in what region?
A
DNA binding domain
14
Q
Caspases
A
Cysteine proteases that set apoptosis in motion
Induce apoptosis
15
Q
Presence of trophic factor
A
PI-3 kinase activates Akt, which phosphorylates bad.
P-Bad is bound by a cytosolic protein, 14-3-3, preventing Bad from inhibiting the antiapoptotitc Bcl-2/Bcl-xl proteins.
Bcl-2/Bcl-xl inhibit Bax channel formation, so cytochrome C stays inside the mitochondria and caspases remain in the inactive (procaspase) forms.
15
Q
Absence of trophic factor
A
Bad (soluble pro-apoptotic protein) binds to and inhibits anti-apoptotis proteins (Bcl-2 and Bcl-x) in the mitochondrial membrane.
This allows a membrane-bound pro-apoptotic protein, Bax, to form channels in the outer mitochondrial membrane leading ot the release of cytochrome C.
In the cytosol, cytochrome C interacts with adapter protein, Apaf-1, and promotes activation of the caspase cascade - leads to cell death
16
Q
The cell cycle
A
17
Q
Entry of cells into S and M phases
A
Strictly regulated
Dependent upon supplies to initiate DNA synthesis and complete replication of the genome
18
Q
Restriction point
A
Major checkpoint late in G1
19
Q
Mitotic cyclins
A
Clyclins A and B bind during the G2 to M transition
20
Q
G1 cyclins
A
Cyclins D and E bind to CDK’s during G1 to S transition
21
Q
Regulation of cyclin-CDK complexes
A
CDK inhibitor proteins (CKIs)
i.e. p21Cip, p27Kip, and p16Ink4
22
Q
E2F
A
Activation is an early event in the transition from G1 to S phase - transcription factor that induces expression of genes needed in S phase
23
Q
Retinoblastoma protein (Rb)
A
Inhibitor of cell proliferation - tumor supressor
Hypo-phosphorylated Rb binds to and inactivates E2F arresting cells in G1 phase
CDK in mid-late G1 (and during S) hyper-phosphorylate Rb causing it to resease E2F (promotes transition of cells from G1 to S
24
Cell arrest in G1 vs. G2
G1 - prevent copying of damaged bases during DNA synthesis
G2 - alows DNA double stranded breaks to be repaired
25
Sensors of DNA damage
Include ATR and ATM
ATR - ataxia talangiectasia and Rad3-related
ATM - ataxia telangiectasia mutated
## Footnote
Both ATM and ATR have kinase activity
26
P53
Transcirption factor necessary for cell cycle arrest due to damaged DNA
Normally p53 is unstable and degraded quickly, so levels are kept very low
DNA damage leads to phosphorylation of p53 - stabilizes p53 - allowing it to accumulate and stimulate transcription of a cyclin-CDK inhibitor gene (21CIP) p21 inhibits cyclin-Cdk activity to halt cell cycle progression
27
What allows for a small number of transcription factors to regulate a wide variety of genes, contributing to cellular diversty
Combinational gene control
28
Maintenance methylase
Methylates CG sequences on the duaghter strands which are paired to methylated CG sequences of the parental strand, so methylation pattern is inherited by daughter cell
29
What can impair fetal DNA methylation during embryogenesis?
Acetaldehyde from alcohol metabolism
30
Malignant tumors
High nucleus to cytoplasm ratio, prominent nucleoli, many mitoses, and relatively little specialized structure
Presence of invading cells in otherwise normal tissue section is the most diagnostic indication of malignancy
31
Cancer can result from the mutations in what classes of proteins?
1. Growth factors and receptors
2. Signal transduction proteins
3. Transcription factors
4. Cell-cycle control proteins
5. Apoptosis proteins
6. DNA-repair proteins
32
Gain of function mutations
pro-oncogenes to oncogenes
## Footnote
Act dominant, only one altered allele will produce and effect in the cell
33
Loss of function mutations
Mutations in tumor supressor genes
## Footnote
They act recessive (usually), both alleles have to be inactivated before the phenotypic effect is produced
34
Tumor supressor genes
Function to halt cell division, induce apoptosis, or repair damaged DNA
35
Coversion of proto-oncogene to an oncogene
Spontaneous or chemical induced GOF mutations that result in a constitutively active protein
**Localized duplication** (gene amplification) of a region of DNA containing a proto-oncogene - > too much gene expressed
**Chromosomal translocations** and **DNA rearrangements** that bring a frowth regulatory gene under control of a different promoter causing over expression of gene
Or produced an actively transcribed fusion gene (part of gene A is combined with part of gene B) resulting in a hyperactive fusion protein
**Infection** by tumor causing viruses
36
The neu receptor
aka ErbB-2 or HER2 (human epidermal growth factor receptor 2) can undergo mutation that alters a single amino acid in the transmemebrane region, resulting in an RTK with constitutive tyrosine kinase activity
37
Herceptin
mAb directed against HER-2 receptor
38
Loss of the EGF-binding domain of HER1
Produces a truncated protein with unregulated tyrosine kinase activity
These cells are stimulated to proliferate even at concentrations of EGF that do not stimulate normal cells
38
Cetuximab
mAb that targets HER1 and is used to treat certain cancers, including colorectal and head and neck cancers.
By inhibiting HER1, it helps to slow down or stop the growth of cancer cells.
39
Ras signaling pathway
| Diagram
40
Mutations in Ras that reduce its GTPase activity
Ras stays active longer than normal - oncogenic
41
GOF mutation in guanine exchange factors (GEFs)
Result in hyperstimulation of Ras signaling
42
LOF mutations in GTPase activating proteins (GAPs)
Will prolong Ras signaling
GAPs are tumor supressors
NF1 encodes a GAP that accelerates GTP hydrolysis of Ras
Loss of NF1 function allows Ras to remain in its activated GTP-bound state longer than normal
Individuals with **neurofibromatosis** inherit one mutant NF1 allele, but do not develop neurofibromas until a second somatic mutation occurs in the other NF1 allele of a cell. The loss of both functional NF1 alleles in the same cell leads to uncontrolled cell growth and the formation of tumors, such a neurofibromas
43
Proto-oncogenes of the restriction point
**Cyclin D1** becomes an oncogene when it is overexpressed or amplified, leading to excessive activation of the cell cycle. This drives uncontrolled cell division, contributing to cancer development by bypassing the normal regulatory mechanisms.
44
Retinoblastoma gene
RB1is a tumor suppressor, when RB is mutated, E2F is unchecked, leading to uncontrolled cell division and contributing to the development of retinoblastomas. RB is a tumor suppressor; loss of both alleles is needed in the cell for transformation
45
SV40 DNA tumor virus
Encodes a protein called large T antigen that inhibits two tumor suppressor proteins, Rb and p53, that normally halt cell proliferation.
Large T causes tumors in primates
46
Human Papillomavirus (HPV)
Expresses two separate proteins; E6 which binds p53, and E7 which binds Rb. If the E6/7 viral genes accidentally integrate into the host genome they can be overproduced in an unregulated fashion resulting in cancer
47
Acute transforming retroviruses
When a pro-virus integrated next to a proto-oncogene. As the viral genome was copied, part of the proto-oncogene was also copied due to read-through transcription.
The proto-oncogene then underwent a GOF mutation that converted it into an oncogene
48
Rous Sarcoma Virus (RSV)
Causes fibrosarcomas (in chickens, not humans). RSH was the first characterized retrovirus
Three structural genes (gag, pol, env, and v-src)
V-src is required for cancer induction
49
50
c-src
proto-oncogene nearly identical to v-src which is a protein-tyrosine kinase
v-Src is an oncogene - truncated or mutated at the C-terminus which removes regulatory domain in c-src
51
Human T-cell lymphotropic Virus type 1 (HTLV-1)
A retrovirus that cuases adult T-cell leukemia/lymphoma (ATLL). HTLV-1 contains a regulatory gene, tax, that is a transcriptional activator.
Tax disrupts a cellular tumor suppressor pathway and enhances the expression of proto-oncogenes contributing to transformation
52
Chromosomal transolacations that cause transformations
1. Placing a proto-oncogene under control of a different gene promoter leading to over expression - Burkitt's lymphoma
2. Creating a fusion (frankenstein) protein - Chronic myelongeous leukemia
53
Burkitt's lymphoma
B-cell non-Hodgkin lymphoma that results from t(8:14)
c-myc - proto-oncogene, on ch 8 is placed next to an immunoglobulin gene promoter on ch 14. Since immunoglobulins are highly expressed in B-cells, c-myc is now highly expressed. C-myc activateds expression of genes that drive cells through the G1-S transition.
54
Chronic myelogenous leukemia (CML)
t(9:22)
ch 9 carries the**c-abl gene** - tyrosine kinase
Flanking region on ch22 carriers the **N-terminus of the BCR gene**
BCR-Abl fusion protein has **consitutive tyrosine kinase activity** resulting in phosphorylation of proteins that are not normally substrates of Abl. These proteins are activated to drive excessive proliferation of a clone of hematopoeitic cells in bone marrow.
55
Classes of proteins that function as tumor supressors
Checkpoint control proteins that halt cell cycle progression (i.e. Rb and p53)
CDK inhibitor proteins (p16 and p21CIP)
Receptors for hormones the inhibit cell proliferation (i.e. TGF-beta receptors)
Pro-apoptotic proteins
DNA repair enzymes
56
Prominent Tumor Suppressors
Retinoblastoma - spontaneous vs hereditary
P53
Adenomatous polyposis coli (APC gene)
Neurofibromatosis type 1 (NF1 gene)
57
Genomic instability
When cells bypass senscence and telomeres become critically short
Exposed chromosome ends are seen as DNA breaks and the cell tries to repair these
Creates a highly mutagenic environment
58
PD-1 Receptor
Programmed Death-1
Receptor primarily expressed on activated T cells
59
PD-L1
Programmed death ligand-1
Expressed on various healthy/normal cell types
## Footnote
Many cancers upregulate PD-L1 to hide from immune system
60
What tumor supressor gene is negative-dominant?
p53
61
Familial adenomatous polyposis
1. LOF of adenomatous polyposis coli (APC) gene (a series of mutations, including activation of Ras - specifically K-ras)
2. Loss of another TS gene - deleted in colon carcinoma (DCC) gene
3. Loss of p53
62
Murine mAbs
100% mouse proteins
High risk of hypersensitivity rx'ns
Suffix -omab
63
Chimeric mAbs
~65% human
suffix = -ximab
64
Humanized mAbs
~95% human
suffx = -zumab
65
Human mAbs
100% human Abs
suffix = -mumab
## Footnote
Produced in humans or transgenic mice
66
Imatinib mesylate (Gleevec)
1st cancer drug targeted to singal-transducing protein unique to cancer cells - (BCR-Abl)
Highly lethal to CML cells
## Footnote
2nd gen AbI kinase inhibitors - Dasatinib/Nilotinib are used against Gleevec-resistant tumors
67
Small molecule inhibitors of the Tyr kinase activity of the EGF receptor (EGFR/HER1)
Geftinib (Iressa)
Erlotinib (Tarveca)
68
mAb that binds human EGF receptor 2 (HER-2)
Trastuzumab (Herceptin)
69
mAbs that bind to the external portion of EGFR to prevent binding of growth signals?
Cetuximab (Erbitux)
Panitumumab (Vectibix)
70
What small molecule drug activates apoptosis of cancerous cells?
Bortezomib (Velcade)
Interferes with the proteasome - accumulates damaged proteins and triggers apoptosis
71
What drugs target angiogenesis to Tx cancer?
Bevacizumab (Avastin) - binds to the VEGF to prevent angiogenesis
Sorafenib (Nexavar) and sunitinib (Sutent) - small molecule inhibitors of Tyr kinases involved in VEGF signaling
72
Rituximab (Rituxan)
mAb that Tx's certain B-cell nonHodgkin lymphomas
Recognizes CD20 on B cells, binds and triggers an immune response resulting in their destruction
73
mAbs that bind to PD-1 and PD-L1
PD-1 is Tx'd by nivolumab (Opdivo)
PD-L1 Tx'd by pembrolizumab (Keytruda)
74
The absence of growth factors (trophic factors) activates apoptosis by which of the following events?
A) Stimulation of Akt/PKB phosphorylation of Bad
B) Activating cleavage of proscaspases to mature caspases
C) Closing of Bax channels in the mitochondria
D) Increasing the binding of 14-3-3 pfogdin go Bad
75
HPV may cause cervical cancer when ________
A part of the HPV genome inadverntently integrates into the host cell DNA and is averrantly expressed
## Footnote
HPV is a DNA virus
76
Which protein functions to halt the cell cycle if damaged DNA is detected?
p53
77
Gain of function mutation in the Ras proto-oncogene
Loss of GTPase activity
78
What enzyme is responsible for preserving DNA methylation patterns during cell division in eukaryotes?
Maintenance methlase
79
Sorafenib (Nexavar) is a treatment for metastatic renal cancer. What is its mechanism of action?
Inhibits tyrosine kinase activity of some receptor tyrosine kinases as well as a member of the MAP kinase pathway (MAKKK, Raf).
So**raf**enib
80
In the progression of familial adenomatous polyposis (FAP), what is the only gain of function mutation?
GOF of the K-Ras gene
81
A patient with unresectable, locally advanced, metastatic non–small cell lung cancer undergoes treatment with Bevacizumumab (Avastin). After 6 cycles, tumor growth has halted. The most likely reason for the absence of disease progression in the patient is?
Reduction of tumor-induced angiogenesis due to blockade of Vascular Endothelial Growth Factor (VEGF) signaling.
82
What familial cancer results from an inherited defect in the tumor suppressor gene, p53?
Li Fraumeni syndrome
83
Both familial adenomatous polyposis colon cancer and smoking-related lung cancer often involve inaction of what gene?
p53
84
85
86
87
88
89
