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BMS > Hypoxia and Hif1 protein > Flashcards

Hypoxia and Hif1 protein Flashcards

1
Q

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

A

Hypoxia

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2
Q

Occurs in rapidly proliferating tissues and during embryonic development

A

Oxygen depletion

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3
Q

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

A

Hypoxia

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4
Q

Increases vascular growth and restores oxygen nutrient supply

A

Angiogenesis

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5
Q

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

A

Transcriptional, post-transcriptional, and degradation mechanisms

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6
Q

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

A

α-subunit

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7
Q

The activation of Hif1 occurs under

A

Hypoxia conditions

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8
Q

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

A

Oxygen depletion

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9
Q

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

A

Hydroxylation

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10
Q

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

A

von Hippel-Lindau (VHL) Factor

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11
Q

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

A

Hydroxylated Hif1α

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12
Q

In hypoxia conditions the hydroxylase is not

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

A

Activated

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13
Q

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

A

Hypoxia in normal physiological state

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14
Q

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

A

Low oxygen or hypoxia

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15
Q

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

A

Hypoxia

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16
Q

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

A

Organs, tissues, or cells

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17
Q

A reduction in oxygen supply, as caused at

high altitude or lung disease can cause

A

Hypoxia

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18
Q

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

A

Hypoxia

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19
Q

Can create hypoxic regions in most solid tumors

A

Severe structural abnormality of tumor microvessels

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20
Q

Needed for ATP production

A

Oxygen

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21
Q

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

A

Energy (ATP)

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22
Q

What are the three phases of acclimatization to high altitude?

-All mediated by Hif1

A

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

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23
Q

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

A

Hif transcription factor

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24
Q

A way to make tissues get more oxygen

A

Angiogenesis

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25
Q

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

A

Nucleus

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26
Q

The beta subunits are stable

A

Nucleoproteins

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27
Q

Hif1 protein synthesis is promoted by

A

mTOR/S6-kinase

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28
Q

Hif1 degradation is controlled by

A

VHL and VDU

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29
Q

Post-translational modifications of Hif1 that promote degradation include

A

Prolyl hydroxylation and lysyl acetylation

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30
Q

Occurs by both VHL-dependent and VHL-independent mechanisms

A

Hif1 degradation

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31
Q

Which post translational modification promotes Hif1 transcription?

A

Cystine nitrosylation

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32
Q

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

A

VHL

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33
Q

Can dismantle a multi-Ub chain conjugated to Hif1

A

VDU2

34
Q

Multi-Ub Hif1 is degraded by the

A

Proteasome

35
Q

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

A
  1. ) Degrade the proline hydroxylases (PDH)
  2. ) Ubiquinate and degrade VHL/E3 ligase
  3. ) deubiquinate the ubiquinated Hif1 with VDU
36
Q

What three things make up the hypoxia response?

A
  1. ) Angiogenesis
  2. ) Energy Metabolism
  3. ) Inflammation
37
Q

Hif1α and Hif2α are constitutively unstable proteins that reside in the

A

Cytosol

38
Q

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

A

Hif1α subunit

39
Q

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

A

Hyper-proliferating cells (cancer cells)

40
Q

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

A

von Hipple Lindau tumor suppressor protein

41
Q

VHL is the substrate-recognition component of a complex

A

Ubiquitin 3 ligase

42
Q

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

A

Kidney, Retina, and CNS

43
Q

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

A

VDU2

44
Q

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

A

Ubiquitin/proteasome system

45
Q

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

A

Hypoxia

46
Q

VHL stability is also tightly regulated by ubiquitylation by

A

UCP E3 enzyme

47
Q

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

A

Degredation of hydroxylated Hif1α by the VHL pathway

48
Q

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

A

Translational control

49
Q

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

A

Hif1α protein levels

50
Q

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

A

Cell surface tyrosine kinase receptors

51
Q

Signaling through the PI3k mechanism requires

-promote translation of mRNA’s encoding Hif1α

A

mTOR and S6-kinase

52
Q

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

A

Stabilize it

53
Q

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

A

aHif

54
Q

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

A

aHif and Hif1α

55
Q

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

A

Inflammatory response

56
Q

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

A

microRNAs

57
Q

Selectively inhibit normoxia genes during hypoxia

A

microRNAs

58
Q

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

A

Growth regulating metabolic activities

59
Q

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

A

Carbohydrate metabolism

60
Q

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

A

Pyruvate

61
Q

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

A

TCA cycle and electron transport chain

62
Q

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

A

Anaerobic pathway

63
Q

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

A

Hif1α

64
Q

Low oxygen tension in tissues results in increased activity of

A

Tissue macrophages

65
Q

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

A

Hypoxia

66
Q

This hypoxia response is coupled to innate immunity mediated by

A

NF-kB signaling

67
Q

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

A

IκB Kinases (especially IKK-β)

68
Q

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

A

IKK-β

69
Q

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.

A

NF-κB

70
Q

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

A

Hif1 levels or activity

71
Q

Hif1 protein levels were reduced in cells deficient in

A

IKK-β

72
Q

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

A

Hif1 and NF-kB pathways

73
Q

Hif1 mRNA expression can be stimulated by

A

NF-kB transcription activation

74
Q

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

A

Proteosomes

75
Q

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

A

Proteasome

76
Q

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

A

Ub/proteasome

77
Q

Degradation of the inhibitor IkBα requires the

A

Ub/proteasome

78
Q

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

A

Inhibit translation

79
Q

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

A

Anaerobic metabolism

80
Q

Energy metabolism regulators, including Akt, promote the synthesis of

A

Hif1

BMS (62 decks)

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