Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Hypoxia Exam > HIF mechanism and regulation > Flashcards

HIF mechanism and regulation Flashcards

1
Q

Oxygen is an essential component for life on earth

A

proving a fundamental element in the survival of aerobic organisms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

In healthy humans

A

physiological oxygen gradients exist throughout the tissues and cells of the body

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

The partial pressure of oxygen (PO2) in the atmosphere

A

sits at approximately 156mmHg

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Dropping to 100mmHg in the alveoli and

A

as low as 25mmHg in the retina

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

These respective oxygen levels are normal for these regions

A

facilitating cellular respiration by the mitochondria of each cell to generate energy in the form of ATP through oxidative phosphorylation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

In normal oxygen environments

A

mitochondria consume 90% of the O2 available achieving a net production of 34 ATP per glucose molecule through oxidative phosphorylation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

However in circumstances

A

such as travelling to high altitude or in certain lung diseases tissues and cells of the body can become hypoxic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Hypoxia is defined as the physiological condition whereby

A

oxygen demand exceeds available supply

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

insufficient ATP production by mitochondria during hypoxia can

A

alter cellular homeostasis ultimately leading to a state of bioenergetic crisis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

during chronic hypoxic conditions

A

cells can experience oxidative stress due to impaired energy production

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

knock on effects such as

A

cell death, tissue damage and organ dysfunction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

to prevent these drastic consequences therefore

A

animals have evolved the ability to adapt to chronic hypoxia on a cellular level in order to ensure homeostasis and survival

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

hypoxia inducible factor (HIF)

A

highly conserved
heterodimeric TF
exists in 3 isoforms
HIF-1, HIF-2, HIF-3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

HIF-1

A

central player in cellular response to hypoxia
constitutive B subunit
oxygen-sensitive a subunit

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

discovery of HIF-1 pathway

A

combination effort by three clinician scientists
Gregg Semenza
Peter Ratcliffe
William Kaelin Jr

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

shared 2019 nobel prize in phys or medicine for

A

seminal research on how cells sense and adapt to oxygen availability

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

In physiological normoxia…. 90%

A

90% oxygen consumed by mitochondria to produce ATP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Remaining 10%

A

used in degradation of constitutively expressed HIF1a mRNA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

In normoxic conditions… prolyl

A

prolyl hydroxylase domain (PHD) enzymes use oxygen as substrate in order to add specific proline residues to the O2 dependent degradation domain (ODD) of the HIF-1a subunit (ratcliffe and kaelin, 2001, independently)

20
Q

PHD also exists in three isoforms

A

PHD1, 2, 3
Can hydroxylate 2-oxyglutarare
Ascorbate
Iron

21
Q

Hydroxylated HIF-1a recognised and targeted for…..

A

proteosomal degradation by the von hippel lindau (VHL) tumour suppressor protein

component of the E3 ubiquitin lipase complex (maxwell and ratcliffe, 1999)

22
Q

in particular, hydroxylation of the proline 564 on HIF-1a

A

is critical for VHL interaction (Jaakola, 2001)

23
Q

factor inhibiting hif (FIH)

A

is a second enzyme involved in HIF regulation where hydroxylation of asparagine residues on HIF1a blocks association with transcriptional activators CBP/p300 to inhibit transcriptional HIF activation

24
Q

Thus together, 2-oxyglutarate-dependent-dioxygenases…..

A

PHD and FIH work effectively to prevent accumulation and transactivation of the HIF1 pathway in normoxic conditions

25
Q

In hypoxic conditions….mito

A

mitochondria consume 100% of the oxygen available to the cell in order to maintain cellular respiration

26
Q

HIF degradation by oxygen-dependent hydroxylases is prevented

A

in hypoxic conditions

27
Q

the oxygen-dependent hydroxylation of HIF1a subunit by……

A

PHD and FIH is reduced resulting in rapid HIF1a stabilisation and accumulation

28
Q

HIF1a migration into the nucleus and dimerisation with…..

A

HIF1B to induce an adaptive transcriptional response through CBP/p300 interaction (Semenza, 1993)

29
Q

HIF complex binds to hypoxia response elements (HRE)…..in

A

promoter regions of target genes to promote transcription of genes involved in adaptive responses to hypoxia (Semenza, 1992)

30
Q

Target genes

A

VEGF (angiogenesis)
iNOS (vasodilation)
EPO (erythropoiesis)
glycolytic enzymes, GLUT1&3, LDH (glycolysis)

31
Q

HIF master regulator

A

associated with regulation of over 200 genes in adaptive cellular response to hypoxia

32
Q

Promotion of erythropoiesis

A

EPO stimulates production of RBC in response to low O2 enhancing oxygen carrying capacity of blood and ensuring efficient oxygen delivery to tissues and supporting cellular adaptation to hypoxia

33
Q

Formation of new blood vessels (angiogenesis)

A

vascular endothelial growth factor (VEGF)
promotes development of extensive vascular network
enhance oxygen supply to tissues
cell survival and function

34
Q

vasodilation (iNOS)

A

increase blood flow
optimise O2 transport to tissues
support tissue oxygenation
cellular function under hypoxic conditions

35
Q

in combo, EPO, VEGF and iNOS….

A

results in net oxygen delivery to tissue in order to maintain survival

36
Q

HIF mediates glycolysis…..the metabolic

A

the metabolic pathway involved in generation of energy without relying on oxygen-dependent processes

37
Q

under hypoxic conditions HIF promotes expression of glycolytic enzymes…

A

facilitating the conversion of glucose to ATP in the absence of oxygen

38
Q

metabolic adaptation ensures cellular energy production…

A

in oxygen deprived environments

39
Q

HIF upregulates glucose transporters

A

GLUT1&3

40
Q

Increased LDH expression…

A

to ensure efficient conversion of pyruvate to lactate preventing buildup of pyruvate in absence of TCA cycle and allowing glycolysis to proceed

41
Q

In this way HIF promotes….

A

ATP production in order to maintain cellular homeostasis

42
Q

While the HIF pathway is highly adapted and regulated mechanism in cellular response to hypoxia

A

dysregulation involves VHL disease

43
Q

VHL disease is a rare genetic disorder…

A

caused by defective oxygen dependent gene expression

44
Q

In VHL disease, the cell believes…

A

it is hypoxic when it is not leading to aberant HIF pathway activation triggering expression of genes involved in various cellular responses to hypoxia

45
Q

Processes triggered in VHL disease

A

angiogenesis
erythropoeisis
glycolysis
adaptive mechanisms

46
Q

patients with VHL disease suffer an increased risk of….

A

tumour and cyst development
especially in highly vascularised tissues

47
Q

hemangioblastomas

A

hallmark feature of VHL
high predisposition to developing these vascular tumours in CNS
brain and spinal cord

Hypoxia Exam (9 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions