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Flashcards in Unit III Deck (125):
1

Anchorage Independence

The ability to grow without attachment to solid substrate.

A property of cancer cells.

2

Five different properties of malignant cancer cells

1. Anchorage Independence
2. Immortalization - can proliferate indefinitely
3. Loss of contact inhibition - ability to grow over one another
4. Insensitivity to anti-growth signals
5. Tissue invasion and metastasis

3

Multi-step process for cancer

1. Noraml cell
2. Inreased proliferation
3. Early/ progressive neoplasia
4. Carcinoma - tumor developed
5. Metastatsis - spreading through the circulatory system
6. Turn on oncogene
7. Turn off tumor suppressor (both cell cycle regulatory and DNA repair genes).
8. Turn off apoptotic genes

4

What types of genes are usually mutated in tumor initiation?

Oncogenes and Tumor Suppressors

5

Familial Rb is more prone to what type of tumor?

Bilateral

6

Sporadic Rb is prone to what type of tumor?

Unilateral.

It's much more unlikely to have the same two sporadic muations in both eyes.

7

Rb within the cell cycle

is an inhibitor of cells moving from the G1 to S phase

8

Inhibitor of Rb?

Cyclin D and E which phosphorylate Rb

9

How does loss of heterozygosity occur?

1. Mutation
2. Mitotic recombination
3. Chromosome loss
4. and/or environmental factors

10

Explain the Knudson Theory

If you're heterozygous, you have one strike against you through your genes ( one copy of suppressor gene knocked out in your parents' passed on DNA). If you have another "strike" (such as UV exposure causing an unrepaired mutation in the other copy), you're unable to produce that tumor suppressor gene at all - leads to cancer.

11

Ways to inactivate tumor suppressor

Translocations
Loss of heterozygosity - RB

12

Examples of dominant inherited cancer

Familial Retinoblastoma (RB)
Adenomatous Polyposis (FAP-APC gene)
Familial Breat and Ovarian Cancer (BRCA1 and BRCA2 genes)
Wilms tumor

13

Examples of Recessive inherited cancer

Xeroderma Pigmentosa (XP genes)
Aataxia-Telangiectasia (AT gene)
Bloom's syndrome
Fanconi's Congenital aplastic anemia (FA genes)

14

Describe the inheritance pattern of Rb

It is an autosomal dominant disorder (consistent when drawing a family pedigree) however, it is a RECESSIVE disorder in which loss of heterozygosity and removal of both Rb genes in a cell leads to uncheck proliferation of cells

15

Is Rb an oncogene or tumor suppressor?

tumor suppressor (anti-oncogene)

16

Function APC gene

encodes a cytoplasmic protein that keeps beta-catenin outside the nucleus; without APC, beta-catenin goes into the nucleus and beings uncontrolled transcription of oncogenes like c-myc.

17

Function of the BRCA 1 gene

Breast Cancer Gene 1: encodes scaffold protein that checks the cell cycel to make sure that DNA has replicated correctly. When this gene is mutated, this surveillance on the cell cycle is removed.

18

What type of gene is BRCA1 and 2?

tumor suppressor

19

What type of gene is p53

Originally thought to be an oncogene because a p53 mutation was dominant to the wild type gene in producing cellular transformation. Now we know that the p53 mutation produces a mutant PROTEIN that binds to the wild type p53 to inactivate it - CLASSIC TUMOR SUPPRESSOR.

20

What gene is referred to as "spoiler" or "monkey wrench"?

p53

21

Why is p53 considered the "guardian of the genome"?

1. Acts as a transcription factor which prevents cells from replicating damaged or foreign DNA
2. It is required for cell apoptosis, cells with damaged DNA commit suicide
3. Interferes with the life cycle of human viruses including Adenovirus and HPV

22

What genes does HPV try to inactivate?

Rb and p53

23

What are the three genes found in a viral RNA?

1. gag gene
2. env gene
3. poly gene

24

Function the gag gene?

Found in viral RNA
codes for internal virion protein

25

Function of the env gene?

Found in viral RNA
codes for viral membrane glycoproteins

26

Function of the pol gene?

Found in viral RNA
codes for a virus polymerase

27

What gene is needed to produce sarcoma?

v-onc gene segment

28

HPV E6

protein that inhibits p53

29

HPV E7

protein that binds to and inhibits Rb

30

function of pp60v-src

A protein coded by the v-src oncogene and is a membrane-bound protein kinase that phosphorylates tyrosine residues. Changes the properties of cells by affecting gene expression

31

function of the v-erb-B

Oncogene that codes for a protein that is similar in structure to the cell surface receptor for epidermal growth factor (EGFR).

32

v-abl

oncogene that codes for a protein kinase that phosphorylates tyrosine residues on other proteins.

33

v-src

oncogene of Rous Sarcoma Virus causing fibrosarcomas in birds

34

v-myc

oncogene usually fused with portion of the gag gene. Capable of eliciting neoplastic transformation of cells

35

How are oncogenes used as molecular markers in prognosis?

The level of expression of oncogenes tends to correlate with the rapidity of the progress of the cancer

36

Example of oncogenes used for prognosis?

1. The level of expression of the N-myc gene used in prognosis analysis for neuroblastoma

If you have greater than 10 copies of n-myc death is accelerated

2. HER/neu oncogene encodes integral membrane protein kinase and is amplified in 20% of breast cancers

37

Targeting oncogenes

Herceptin - drug antibody therapy agains the HER2/erb2 oncogene product

Gleevec - inhibits ABL tyrosine kinase specific to the ATP binding site

38

Targeting tumor repressors

Inject RB directly into Rb-negative tumors
Use drug that only kills cells with p53 deficiencies
Use a drug that corrects the mutant conformation of the dominant-negative p53 proteins

39

Diagnostic Criteria for LFS

I. Proband with sarcoma diagnosed before 45 years of age AND
II. A first-degree relative with any cancer under 45 years of age AND
III. A first or second-degree relative with any cancer under 45 years of age or a sarcoma at any age

40

Diagnostic Criteria for Li Fraumeni Like Syndrome

I. Proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed before 45 years of age AND
II. A first- or second-degree relative wit ha typical LFS cancer (sarcoma, breast cancer, brain tumor, adrenal cortical tumor, or leukemia) at any age AND
III. A first- or second-degree relative with any cancer under the age of 60 years

41

What is Von Hippel-Lindau syndrome?

Formation of cystic and vascularized tumors in many organs

42

What is the pattern of inheritance for Von-Hippel Lindau syndrome?

Autosomal dominant

43

What are the major causes of death in patients with Von Hippel-Lindau?

Metastatic Renal Cell Carcinoma
CNS hemangioblastomas

44

Percent of VHL cases caused by sporadic mutations?

20%

45

What type of gene is the VHL gene?

tumor suppressor gene

46

clinical manifestations of Von Hippel-Lindau (VHL) disease.

Cerebellar and spinal cord hemangioblastomas
Retinal hemangioblastomas
Bilateral kidney cysts and clear cell renal cell carcinomas (RCC)
Pheochromocytomas
Pancreatic cysts and pancreatic neuroendocrine tumors
Endolymphatic sac (inner ear) tumors (ELST)
Cystadenomas of the genitourinary tract (epididymal, broad ligament)

47

Type 1 VHL

Type 1: Hemangioblastoma + clear cell renal cell carcinoma
low risk of pheochromocytomas
due to total loss or partial loss of VHL

48

Type 2a VHL

Hemangioblastoma and pheochromocytoma
low risk of renal cell carcinoma
high risk for pheochromocytoma
due to VHL missense

49

Type 2b VHL

hemangioblastoma, clear cell renal cell carninoma, pheochromocytoma (high risk)

due to VHL missense

50

Type 2c VHL

pheochromocytoma only
due to VHL missense

51

Where is the VHL gene located?

chromosome 3 (3p25-26)

52

Actions of the VHL protein?

Regulation of hypoxia inducible transcription factor (HIF)
suppression of aneuploidy
maintenance of primary cilia and stabilization of microtubules

53

HIF under normoxic conditions?

HIF is hydroxylated and is then ubiquitinated by VHL wild type and undergoes proteosomal degradation

54

HIF under hypoxic condition?

HIF does not get hydroxylated and goes straight to nucleus and activate transcription of genes that are involved in angiogenesis (development of new blood vessels), metabolism, apoptosis, and other processes that promote cancer growth and survival under low O2.

factors that affect surrounding vasculature

55

Main mechanism for clear cell renal cell carcinoma?

sporadic mutations
VHL loss or mutation is responsible for about 2/3rd of these sporadic cases
Only 4% of these cases are inherited.

56

Therapies used to treat clear cell renal cell carcinoma?

block thevascular endothelial growth factor (VEGF), m-TOR, HIF-2a inhibitors.

Immunotherapies used to stop the down-regulation of immune system typically seen in cancers.

57

Define ionotropic receptors

Neurotransmitter receptors directly coupled to ion channels (ex: the receptor and channel are part of the same protein).

58

Selectivity of pentameric ligand-gated channels

selective for the permeation of chloride, or allow permeation of both sodium and potassium (with slight preference for sodium)

59

Describe the structure of pentameric ligand-gated channels

Heteropentamers
5 subunits
each subunit has 4 transmembrane alpha helices
M2 alpha helices assembles around the ion-conducting pathway

60

Structure of ionotropic glutamate receptor

tetrameric ligand-gated channels

61

Selectivity of of ionotropic glutamate receptor

two of the four subunits bind glutamate
other two bind glycine

62

Apical Surface

Faces the mucosal lining or lumenal lining. usually contains special transporters

63

Basolateral Surface

Exposed to interstitial fluid and usually has generic transport properties like plasm membranes of non epithelial cells

64

Where is the Na/K pump located?

Basolateral membrane

65

Describe the permeability of Na and K in the basolateral membrane.

low sodium permeability
high potassium permeability

66

Describe the permeability of Na and K in the apical membrane.

highly permeable to sodium
low potassium permeability

67

What is the maximum diameter for transported particles through the nuclear pore complex?

39 nm

68

What is the role of Karyopherins?

They directly interact with the phenylalanine (F) and glycine (G) Nups or with the cargo itself.
Interacts with the nuclear pore complex

69

What source of energy is used to transport mRNA outside of the nucleus?

ATP

70

Smooth ER is important for..?

Making lipids

71

What is the Signal Recognition Particle (SRP)?

It recognizes the signal sequence on a protein and binds to it.
Stops translation until bound by SRP receptor on ER.

72

What is the translocon?

A group of proteins that is a channel that forms a pore from one side of membrane to the other.

73

Type I transmembrane protein

Has COO- group in the cytoplasm and NH3+ group inside the ER

74

What causes Limb Girdle disease and Rippling Muscle disease

A mutation in the caveolin-3 gene which is expressed in skeletal and cardiac muscles

75

What are the two mechanisms that vesicles are formed?

1. clathrin coat proteins
2. caveola

76

When do cells use ubiquitin-proteasome system (UPS)?

rapid degradation of proteins when fast adaptation is needed

Makes up about 1% of protein in cells

77

When do cells use Autophagy?

degradation of long-lived proteins and entire organelles

required for the adaptation to environmental stresses such as starvation

78

What is the function of Heat shock protein 70 (Hsp70)

helps fold a protein by binding to exposed hydrophobic patches in incompletely folded proteins and prevents aggregation

79

What is the function of Heat shock protein 60 (Hsp60)

forms an elaborate, large, barrel-shaped structure that acts
as an isolation chamber. Misfolded proteins are fed into the chamber to prevent aggregation and to help it to
refold.

80

What is the role of Bip?

chaperone protein that functions much like Hsp70 but uses ATP to help proteins fold

81

What is the role of ERp57?

located within the ER and is a a thiol oxidoreductase that allows formation of disulfide bonds

82

What are lectins?

Bind Sugars

83

Example lectins?

Calnexin and calreticulin

84

How many ubiquitins for proteosome to recognize?

4 ubiquitins in a ROW

85

What is the role of E3?

enzyme that transfers ubiquitin from E2 to a lysine in the protein and adds more ubiquitin

86

Order these in terms of the number of genes for these enzymes: E1, E2, E3 (smallest to largest)

E1

87

What is the importance of Nieman Pick disease?

They are resistant to Ebola because they have mutation in cholesterol transfer

88

Significance of proteasomes?

Peptides from these immunoproteasomes are
transported into the ER and bind to MHC class I luminal domains. The MHC class I molecule is a complex with
a transmembrane domain; this complex plus peptide progresses through the secretory pathway until the peptide
is on the extracellular surface of the cell. Immune cells recognize these peptides as self or foreign and
“immunology happens”.

89

Describe the process of Chaperone mediated autophagy.

5 AA motif KFERQ is recognized by Heat Shock Protein 70 (HSP70) which is recognized by a complex of proteins and directly delivered by a lysosomal receptor protein (LAMP-2A) directly into the lysosome, where the proteins are degraded

90

What is an amphisome?

An endosome fused with an autophagosome

91

What gene regulates autophagy?

ATG

92

What effect does rapamycin have on autophagy?

increases autophagy

93

What is the relationship between autophagy and apoptosis?

inversely related

Caspases cleave Beclin 1, switches off autophagy, letting apoptosis work more effectively

94

What is the role of Bcl-2 and Bcl-xL?

Bcl-2 and Bcl-xL bind to BH3 domains on Beclin 1 to inhibit autophagy

95

What is the role of Beclin 1 by itself?

Upregulates autophagy

96

What is the significance of BH3 mimetic ABT 737?

It disrupts the Beclin-1-Bcl-xl interaction and causes apoptosis to occur.

Recent findings are showing autophagy is also occuring so we need to tease this out for future research.

97

What is the significance of phospholipid phosphatidylserine (PS)?

When it is exposed to the outer leaflet macrophages have receptors for PS, and recognize, bind to, and ingest cells that have committed to the apoptotic pathway. Gives the cell no chance to lyse and release inflammation-causing molecules to the extracellular space.

98

What is the role of Bcl-2 and Bcl-XL?

anti-apoptosis

99

What is the role of Bim and PUMA?

pro-apotopic members that move to the mitochondrion and replace Bcl-2 and Bcl-XL. This allows other members of the same family, Bax and Bax, to act on the membrane, making it permeable so it releases cytochrome C into the cytoplasm

100

Caspase-9

signal caspase that activates caspase-3

101

Caspase-3

executioner caspase that cleaves many substrates, eventually resulting in the classic appearance of apoptosis

102

What molecule activates caspase-9?

activated Apaf-1

103

What activates Apaf-1?

cytochrome c in the cytoplasm

104

What is the significance of FAS Ligand?

the CTL upregulates expression of a surface molecule called Fas (or CD95) ligand (FasL, CD95L), which
then engages and cross-links a corresponding molecule on the abnormal cell’s surface, Fas or CD95

105

What is the role of activated Fas or CD95?

CD95 transduces a signal into the cell’s interior, which recruits to CD95 an adaptor molecule called FADD, which activates caspase-8. Caspase-8 then activates caspase-3 for apoptosis to occur?

106

What is the significance of FLIP?

It competes with caspase-8 for binding to FADD, and thus inhibits apoptosis signaling (

107

Define Statins

drugs used to lower cholesterol

108

What is the rate limiting step for the synthesis of cholesterol?

HMGCoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase)

109

What is the significance of sterol regulatory
element binding protein (SREBP)?

Both uptake and synthesis are regulated by the sterol regulatory element binding protein (SREBP), a protein containing a transcription factor that regulates both
LDLR and all 30 of the synthesis proteins.

110

What is the transcription factor used to upregulate cholesterol synthesis?

basic helix loop helix (bHLH) DNA- binding protein that is held inactive because it is part of a larger
transmembrane protein (SREBP). Only activated once it is cleaved off in the Golgi

111

role of Insig and SCAP?

when cholesterol is low, SREBP needs to move to the Golgi, where it is cleaved to release the transcription factor. Insig blocks the SCAP signal to recruit COPII. Therfore, Insig binds to SCAP when cholesterol levels are HIGH.

112

How is BHLH cleaved from SREBP?

via RIP, regulated intramembrane proteolysis within the Golgi

113

What are the three classes of lipids in a membrane?

phospholipids, sphingolipids, and cholesterol

114

What are the most common phospholipids in the membrane?

phosphatidylethanolamine (PE), phosphatidylcholine
(PC), phosphatidylserine (PS), and
phosphatidylinositol (PI).

115

What phospholipids are more prevalent within the inner leaflet of membrane?

Negatively charged phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylinositol (PI)

116

What phospholipids are more prevalent in the outer leaflet?

Phosphatidylcholine PC, sphingomyelin, and glycolipids are

117

Where are most lipids made?

In the endoplasmic reticulum

118

Order these membranes from thin to thickest: ER, Golgi, and Plasma membrane

ER

119

What molecule does your body use to synthesize cholesterol?

acetate

120

What molecule do you need to break up the SNARE complex for recycling?

N-ethylmaleimide Sensitive Factor (NSF)

121

How many ATPs do you need to separate the SNARE complex?

6 ATPs; one for each subunit.

122

What is the role of alpha snap?

It binds to the SNARE complex and recruits NSF

123

What is the role of n-sec1?

binds to syntaxin to refold it and stays bound to prevent VAMP from binding. n-sec1 must be released before another SNARE complex can form.

124

What causes n-sec1 to release itself from syntaxin?

The release of calcium

125

Four major classes of molecules found in ECM

1. glycosaminoglycans --> proteoglycans
2. fibrous proteins such as collagen and elastin
3. fibronectin and laminin
4. Water and many solutes