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Flashcards in Hypoxia and Hif1 protein Deck (80):
1

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

Hypoxia

2

Occurs in rapidly proliferating tissues and during embryonic development

Oxygen depletion

3

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

Hypoxia

4

Increases vascular growth and restores oxygen nutrient supply

Angiogenesis

5

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

Transcriptional, post-transcriptional, and degradation mechanisms

6

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

α-subunit

7

The activation of Hif1 occurs under

Hypoxia conditions

8

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

Oxygen depletion

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

Hydroxylation

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

von Hippel-Lindau (VHL) Factor

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

Hydroxylated Hif1α

12

In hypoxia conditions the hydroxylase is not

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

Activated

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

Hypoxia in normal physiological state

14

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

Low oxygen or hypoxia

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

Hypoxia

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

Organs, tissues, or cells

17

A reduction in oxygen supply, as caused at
high altitude or lung disease can cause

Hypoxia

18

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

Hypoxia

19

Can create hypoxic regions in most solid tumors

Severe structural abnormality of tumor microvessels

20

Needed for ATP production

Oxygen

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

Energy (ATP)

22

What are the three phases of acclimatization to high altitude?

-All mediated by Hif1

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

23

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

Hif transcription factor

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A way to make tissues get more oxygen

Angiogenesis

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

Nucleus

26

The beta subunits are stable

Nucleoproteins

27

Hif1 protein synthesis is promoted by

mTOR/S6-kinase

28

Hif1 degradation is controlled by

VHL and VDU

29

Post-translational modifications of Hif1 that promote degradation include

Prolyl hydroxylation and lysyl acetylation

30

Occurs by both VHL-dependent and VHL-independent mechanisms

Hif1 degradation

31

Which post translational modification promotes Hif1 transcription?

Cystine nitrosylation

32

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

VHL

33

Can dismantle a multi-Ub chain conjugated to Hif1

VDU2

34

Multi-Ub Hif1 is degraded by the

Proteasome

35

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

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

36

What three things make up the hypoxia response?

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

37

Hif1α and Hif2α are constitutively unstable proteins that reside in the

Cytosol

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

Hif1α subunit

39

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

Hyper-proliferating cells (cancer cells)

40

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

von Hipple Lindau tumor suppressor protein

41

VHL is the substrate-recognition component of a complex

Ubiquitin 3 ligase

42

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

Kidney, Retina, and CNS

43

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

VDU2

44

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

Ubiquitin/proteasome system

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

Hypoxia

46

VHL stability is also tightly regulated by ubiquitylation by

UCP E3 enzyme

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

Degredation of hydroxylated Hif1α by the VHL pathway

48

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

Translational control

49

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

Hif1α protein levels

50

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

Cell surface tyrosine kinase receptors

51

Signaling through the PI3k mechanism requires

-promote translation of mRNA's encoding Hif1α

mTOR and S6-kinase

52

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

Stabilize it

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

aHif

54

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

aHif and Hif1α

55

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

Inflammatory response

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

microRNAs

57

Selectively inhibit normoxia genes during hypoxia

microRNAs

58

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

Growth regulating metabolic activities

59

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

Carbohydrate metabolism

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

Pyruvate

61

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

TCA cycle and electron transport chain

62

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

Anaerobic pathway

63

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

Hif1α

64

Low oxygen tension in tissues results in increased activity of

Tissue macrophages

65

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

Hypoxia

66

This hypoxia response is coupled to innate immunity mediated by

NF-kB signaling

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

IκB Kinases (especially IKK-β)

68

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

IKK-β

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.

NF-κB

70

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

Hif1 levels or activity

71

Hif1 protein levels were reduced in cells deficient in

IKK-β

72

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

Hif1 and NF-kB pathways

73

Hif1 mRNA expression can be stimulated by

NF-kB transcription activation

74

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

Proteosomes

75

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

Proteasome

76

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

Ub/proteasome

77

Degradation of the inhibitor IkBα requires the

Ub/proteasome

78

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

Inhibit translation

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

Anaerobic metabolism

80

Energy metabolism regulators, including Akt, promote the synthesis of

Hif1

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