Hypoxia and Hif1 protein

Question 1

Refers to a deficit in oxygen that occurs when the circulatory system fails to provide adequate oxygen to tissues

Answer 1

Hypoxia

Question 2

Occurs in rapidly proliferating tissues and during embryonic development

Answer 2

Oxygen depletion

Question 3

Maladaptive conditions including ischemia, myocardial infarction, and solid tumor growth are associated with

Answer 3

Hypoxia

Question 4

Increases vascular growth and restores oxygen nutrient supply

Answer 4

Angiogenesis

Question 5

A central player in the hypoxia response is the transcription factor Hif1 (and Hif2). The availability of
Hif1 is regulated by

Answer 5

Transcriptional, post-transcriptional, and degradation mechanisms

Question 6

Hif1 is a dimer of alpha and beta subunits. Which one is unstable?

Answer 6

α-subunit

Question 7

The activation of Hif1 occurs under

Answer 7

Hypoxia conditions

Question 8

The level of vascular endothelial growth factor (VEGF) is increased in all tissues in response to

Answer 8

Oxygen depletion

Question 9

Under normoxia conditions, a conserved proline residue in Hif1α is modified by

Answer 9

Hydroxylation

Question 10

The hydroxylated proline lies in the binding interface that interacts with a component of a complex ubiquitin E3-ligase enzyme, called the

Answer 10

von Hippel-Lindau (VHL) Factor

Question 11

Ubiquitinated by the VHL-E3 ligase and degraded by the proteasome

Answer 11

Hydroxylated Hif1α

Question 12

In hypoxia conditions the hydroxylase is not

-stabilized Hif1α subunits bind Hif1β subunits to promote transcription of hypoxia-inducible genes

Answer 12

Activated

Question 13

Physiological tissue oxygen tensions are significantly lower than ambient oxygen tensions as a result of the dramatic decrease in blood oxygen content as it travels from the lungs throughout the body. This is an example of

Answer 13

Hypoxia in normal physiological state

Question 14

Provides the required extracellular stimulus for proper embryogenesis and wound healing, and maintains the pluripotency of stem cells

Answer 14

Low oxygen or hypoxia

Question 15

Plays critical roles in the pathobiology of heart disease, cancer, stroke, and chronic lung disease, which are responsible for 60% of deaths in the United States

Answer 15

Hypoxia

Question 16

Hypoxia that involves oxygen tensions below the normal physiological range can restrict the function of

Answer 16

Organs, tissues, or cells

Question 17

A reduction in oxygen supply, as caused at

high altitude or lung disease can cause

Answer 17

Hypoxia

Question 18

Localized ischemia due to the disruption of blood flow to a given area can cause

Answer 18

Hypoxia

Question 19

Can create hypoxic regions in most solid tumors

Answer 19

Severe structural abnormality of tumor microvessels

Question 20

Needed for ATP production

Answer 20

Oxygen

Question 21

Under hypoxic conditions, the tissues do not have enough oxygen, so the body can not produce enough

Answer 21

Energy (ATP)

Question 22

What are the three phases of acclimatization to high altitude?

-All mediated by Hif1

Answer 22

Immediate, Intermediate (days), and long term (weeks to months)

Question 23

trans-activate the expression of a large number of genes including those that promote angiogenesis, anaerobic metabolism, and resistance to apoptosis

Answer 23

Hif transcription factor

Question 24

A way to make tissues get more oxygen

Answer 24

Angiogenesis

Question 25

In addition to Hifα subunits, there are also constitutive Hifβ subunits which are present in the

Answer 25

Nucleus

Question 26

The beta subunits are stable

Answer 26

Nucleoproteins

Question 27

Hif1 protein synthesis is promoted by

Answer 27

mTOR/S6-kinase

Question 28

Hif1 degradation is controlled by

Answer 28

VHL and VDU

Question 29

Post-translational modifications of Hif1 that promote degradation include

Answer 29

Prolyl hydroxylation and lysyl acetylation

Question 30

Occurs by both VHL-dependent and VHL-independent mechanisms

Answer 30

Hif1 degradation

Question 31

Which post translational modification promotes Hif1 transcription?

Answer 31

Cystine nitrosylation

Question 32

VHL is a component of a complex E3 ligase. Hif1 hydroxylation causes binding to

Answer 32

VHL

Question 33

Can dismantle a multi-Ub chain conjugated to Hif1

Answer 33

VDU2

Question 34

Multi-Ub Hif1 is degraded by the

Answer 34

Proteasome

Question 35

What are three ways we can activate Hif1 under hypoxia conditions?

Answer 35

1. ) Degrade the proline hydroxylases (PDH) 2. ) Ubiquinate and degrade VHL/E3 ligase 3. ) deubiquinate the ubiquinated Hif1 with VDU

Question 36

What three things make up the hypoxia response?

Answer 36

1. ) Angiogenesis 2. ) Energy Metabolism 3. ) Inflammation

Question 37

Hif1α and Hif2α are constitutively unstable proteins that reside in the

Answer 37

Cytosol

Question 38

Three prolyl hydroxylases (PHD’s) in human can target multiple proline residues in Hif1α (Pro-402;Pro-564). During normoxia prolyl hydroxlase attaches oxygen to the -The reaction requires oxygen

Answer 38

Hif1α subunit

Question 39

Preferentially use glycolysis for ATP production, because the mitochondrial electron transport chain is unable to function efficiently when oxygen levels are deficient.

Answer 39

Hyper-proliferating cells (cancer cells)

Question 40

The hydroxylated proline (Pro-402) lies in the oxygen dependent-degradation domain (ODD) that is recognized by the

Answer 40

von Hipple Lindau tumor suppressor protein

Question 41

VHL is the substrate-recognition component of a complex

Answer 41

Ubiquitin 3 ligase

Question 42

Mutation in VHL causes von Hipple Lindau disease which is characterized by highly vascularized solid tumors in the

Answer 42

Kidney, Retina, and CNS

Question 43

A deubiquitylation enzyme that is associated with VHL and can specifically dismantle a multi-ubiquitin chain that is attached to Hif1α

Answer 43

VDU2

Question 44

Moreover, VDU2 can itself become a target for degradation by the

Answer 44

Ubiquitin/proteasome system

Question 45

Since VHL can ligate ubiquitin to both Hif1α and VDU2, whether it ubiquitylates Hif1α or VDU2 has a significant outcome on the cellular response to

Answer 45

Hypoxia

Question 46

VHL stability is also tightly regulated by ubiquitylation by

Answer 46

UCP E3 enzyme

Question 47

There are multiple pathways to mediate Hif1α degradation, some that are oxygen dependent and others that are oxygen independent, but the predominant mechanism is the

Answer 47

Degredation of hydroxylated Hif1α by the VHL pathway

Question 48

Hif1α synthesis during hypoxia is not determined by transcriptional control, but rather by

Answer 48

Translational control

Question 49

Increased by the phosphatidyl-inositol 3-kinase (PI3K) mitogen-activated protein kinase (MAPK) pathway.

Answer 49

Hif1α protein levels

Question 50

The MAPK and other signaling pathways are responsice to cytokines and other growth factors via

Answer 50

Cell surface tyrosine kinase receptors

Question 51

Signaling through the PI3k mechanism requires -promote translation of mRNA's encoding Hif1α

Answer 51

mTOR and S6-kinase

Question 52

The expression of antisense RNA transcript (aHIF) has been reported to bind Hif1α mRNA to

Answer 52

Stabilize it

Question 53

As Hif1α levels increased, its transcription activation function resulted in further increase in expression of -underlying a mechanism to rapidly amplify the cellular response to oxygen stress

Answer 53

aHif

Question 54

Strikingly, with continued expression of aHIF, a time dependent activation of double-stranded RNA degradation activity is induced, resulting in elimination of both

Answer 54

aHif and Hif1α

Question 55

Hif plays a crucial role in activating I-kappa-kinase which then induces the

Answer 55

Inflammatory response

Question 56

Small, non-coding single stranded RNA's that bind and inhibit the translation of mRNA -can also promote the cleavage and degradation of specific mRNA's

Answer 56

microRNAs

Question 57

Selectively inhibit normoxia genes during hypoxia

Answer 57

microRNAs

Question 58

Because cell and tissue growth is directly related to oxygen availability and consumption, the Hif1 factors are intimately integrated with

Answer 58

Growth regulating metabolic activities

Question 59

An important trigger that activates the response to hypoxia is mitochondrial dysfunction, which is closely coupled to

Answer 59

Carbohydrate metabolism

Question 60

When oxygen levels decrease, glycogen accumulates in hypoxic cells. Hif1 the stimulates glucose import and mobilization and promotes glycolysis, leading to elevated levels of

Answer 60

Pyruvate

Question 61

However, hypoxia increases lactate dehydrogenase (LDH) activity which converts pyruvate to lactate, thereby diverting it from the

Answer 61

TCA cycle and electron transport chain

Question 62

Thus, hypoxia results in Hif1-mediated alteration in sugar metabolism, and ATP is generated by the

Answer 62

Anaerobic pathway

Question 63

During hypoxia, the expression of the glucose transporters (GLUT1 and GLUT2) are strongly induced by

Answer 63

Hif1α

Question 64

Low oxygen tension in tissues results in increased activity of

Answer 64

Tissue macrophages

Question 65

Entry of infiltrating neutrophils into tissue affected by bacterial infection is increased in

Answer 65

Hypoxia

Question 66

This hypoxia response is coupled to innate immunity mediated by

Answer 66

NF-kB signaling

Question 67

Following stress, infection and inflammation the IkB inhibitor (of NF-kB) is phosphorylated and degraded by the proteosome. This event is triggered by the activation of

Answer 67

IκB Kinases (especially IKK-β)

Question 68

Normally inhibited by prolyl hydroxylases, but this inhibition is reduced during hypoxia

Answer 68

IKK-β

Question 69

A major inducer of Hif1 protein levels, and mutations (in mice) that cause loss of it reduce expression of vascular endothelial growth factor (VEGF), and also cause significant accumulation of bacterial infection in macrophages.

Answer 69

NF-κB

Question 70

Importantly, increasing expression of NF-κB in the absence of hypoxia does not affect

Answer 70

Hif1 levels or activity

Question 71

Hif1 protein levels were reduced in cells deficient in

Answer 71

IKK-β

Question 72

Prolyl hydroxylase (PHD) dependent regulation of IKK-β catalytic activity is critical for response to both infection and oxygen stress thereby linking the

Answer 72

Hif1 and NF-kB pathways

Question 73

Hif1 mRNA expression can be stimulated by

Answer 73

NF-kB transcription activation

Question 74

The presentation of antigens by antigen presenting cells (APC's) requires proteolytic processing of foreign pproteins by

Answer 74

Proteosomes

Question 75

The maturation of the NF-kB transcription factor involves limited degradation by the

Answer 75

Proteasome

Question 76

Activation of the IkB kinase (IKK-β) requires the activity of the

Answer 76

Ub/proteasome

Question 77

Degradation of the inhibitor IkBα requires the

Answer 77

Ub/proteasome

Question 78

Hif1α activates the expression of microRNA’s that bind to mRNA’s in a sequence-specific manner to

Answer 78

Inhibit translation

Question 79

Hypoxia conditions result in metabolic changes that favor i.e. accelerate glycolysis, activate conversion of pyruvate to lactate, block conversion of pyruvate to acetyl-CoA

Answer 79

Anaerobic metabolism

Question 80

Energy metabolism regulators, including Akt, promote the synthesis of

Answer 80

Hif1