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BIOC 311 > Hormonal Regulation (Lecture 33) > Flashcards

Hormonal Regulation (Lecture 33) Flashcards

1
Q

Metabolic regulation in complex organisms

A

Short term regulation (seconds, minutes) = achieved through allosteric control (ie. level
of metabolites) and post-translational modifications (ie. phosphorylation) of enzymes
under hormonal control (eg. catecholamines, insulin)

  • Long term regulation (hours, circadian cycle, seasons, development, aging, etc.) =
    requires transcriptional regulation of metabolic genes
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2
Q

Transcriptional Control of Metabolism

A

Requires specific signals to be transduced to nucleus where individual genes or entire gene
networks are targeted for regulation

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3
Q

Important Aspects of transcriptional control of specific metabolic responses:

A
  • Events upstream of transcriptional activity => signals involved (eg. glucagon, glucocorticoids) and their route to the nucleus (eg. signalling pathways, protein cleavage, direct activation)
  • Molecular mechanisms by which transcription factors regulate gene expression
    Eg. recruitment of polymerase, enzymatic activity of coregulators
  • Events downstream of transcription => depend on genes being targeted and which further signals are generated
    Eg. expression of metabolic enzymes or cascade of regulators
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4
Q

Metabolic Transcription Factors

A

Bind DNA and receive signals to tell TFs to activate/repress transcription

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5
Q

Nuclear Receptors

A

family of 48 ligand-responsive “zinc fingers” transcription factors

  • Many members work as a metabolic sensor involved in all aspects of metabolism
    (carbohydrate, lipid, amino acid, etc.)
  • Most NRs are directly activated by their ligands => hormones will enter nucleus from outside of cell and directly bind receptor
  • Can also be regulated by post-translational modifications
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6
Q

CREB (cAMP Response Element Binding)

A

CREM and ATFI

“leucine zipper” TF activated by phosphorylation by PKA in response to increased cAMP levels following glucagon action

  • Considered first responders in activation of gluconeogenesis during fasting
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7
Q

CEBP (CCAAT-enhancer binding protein)

A

basic “leucine zipper” TF
- Activity is constitutive
- Signal-independent high expression in liver plays major role in response to
fasting

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8
Q

Forkhead Box Proteins

A

FoxO1, FoxO3, FoxO4, FoxO6, FoxA2)

involved in hepatic (liver) glucose production after nutrient deprivation

  • Factors are activated by post-translational modifications such as phosphorylation and acetylation
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9
Q

SREBP-1c (sterol response element binding protein)

A

bHLH-leucine zipper TF that targets genes involved in lipid metabolism

  • Involved in cholesterol synthesis
  • It is activated by proteolytic cleavage stimulated by sterols and unsaturated FAs

=> dormant in ER, low sterol levels activate protein which is trafficked to Golgi, recruties protease that cleaves twice and sends small part to nucleus for transcriptional activation of genes involved in sterol synthesis

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10
Q

hREBP (carbohydrate response element binding protein)

A

bHLH-leucine zipper TF phosphorylated by PKA

  • Responsive to glucose
  • Phosphorylated ChREBP via PKA= inactive ChREBP
  • Activated by removal of phosphate groups by PP2A phosphatase
  • Regulates glucose and lipid metabolism
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11
Q

Metabolic Coregulators

A
  • Do not bind DNA, interact with TFs and or other coregulators
  • TF binding proteins recognize and bind DNA sequence but coregulators are the moiety which activate or repress gene expression
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12
Q

NCOA

A

nuclear receptor coactivator

Aka SRC, steroid receptor coactivator

Family of 3 members involved in all aspects of metabolism (lipid, carbohydrate, aa)

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13
Q

NCOR 1 and 2

A

nuclear receptor corepressor

Two corepressors that often oppose action of NCOAs and other co-activator proteins

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14
Q

RIP140 = aka NRIP1

A
  • Action as repressor decreases mitochondrial biogenesis and oxidative metabolism in muscle
  • Especially at rest
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15
Q

PGC-1alpha and beta

A

master co-activators that interact with multiple transcription factors, most predominantly the nuclear receptors PPARs and ERRs

  • Required for mitochondrial biogenesis, oxidative metabolism and heat production by brown fat
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16
Q

KAT2A and B

A

lysine acetyltransferase Aka GCN5 and PCAF, which are histone acetyltransferases

  • KAT2alpha acetylated PGC-1alpha to decrease its activity and blunting PGC-1alpha
    induced gluconeogenesis
17
Q

HDACs

A

large family of histone deacetylases with broad roles in metabolic control

  • Recruitment of HDAC3 by nuclear receptor Rev-Erb-alpha (clock gene) inhibits expression of lipogenic genes
18
Q

CRTCs

A

family of 3 proteins that act as coactivators of CREB

Regulate CREB-dependent hepatic gluconeogenic program

19
Q

PRMTI

A

methylates nuclear receptors,

  • in particular HNF-4alpha
20
Q

SRTI

A

a sirtuin, NAD+-dependent deacetylase that targets PGC-1alpha, ERRalpha and other coactivators

Affect mitochondrial function

21
Q

Nuclear Receptors

A

Are regulators of metabolism

Protypic TF to study gene regulation

Clinically relevant =>Targets of several drugs to control metabolism

Some are in cytoplasm, bind hormones and move to nucleus

Others are already bound to DNA in nucleus, awaiting hormonal signalling

Recruit coactivators which change expression of target genes

Transcribe genes that will affect metabolic activity

Nuclear receptors and other TFs do not have enzymatic activity; their function is to
recruit co regulatory proteins on DNA to activity transcription

22
Q

what are the ligands for nuclear receptors

A

hormonal ligans and metabolic ligands

23
Q

DHT

A

male steroid hormone, anabolic steroid for building muscle/strength

24
Q

Estrogen

A

female steroid hormone, involved in metabolic pathway, preparing for development of embryo, fat metabolism, change in metabolism associated with estrogen decrease at menopause often leads to weight gain

25
Q

cortisol

A

corticosteroid expressed in all tissues and regulate glucose

metabolism via glucocorticoid receptor

26
Q

Thyroid hormone

A

important in regulating metabolism; hyperthyroidism => high

metabolism, lose weight, opposite can also happen

27
Q

3 main elements of nuclear receptors

A

DNA. binding domain

modulator

ligand binding domain

28
Q

modulator function

A

the modulator is located at the N terminus and functions to modulate receptor activity. this is the target for phosphorylation and it receives signals through phosphorylation and acetylation. a trans activation through coregualttion interaction (AF-1) also occurs at this site

29
Q

DNA binding domain

A

DNA binding domain recognizes a specific sequence of DNA

it is composed of zinc fingers and requires dimerization

30
Q

ligand binding domain

A

receives signals from ligands when bound to the nuclear receptor

can form homo and hetero dimers

transactivation (AF-2) where the coavtivators bind to the receptors for coregualtion interaction

31
Q

Nuclear receptors recognize specific DNA sequences near metabolic genes

A

Nuclear receptors recognizes hormone response element (HRE)

32
Q

methods of recognizing the HRE

A

Monomer can recognize extended half site

Dimers can recognize two sites

Homodimers act on inverted repeats

Heterodimers act on direct repeats

33
Q

core motifs

A

AGGTCA (TGCCT)

AGAACA (TGTTCT)

34
Q

Genome-wide identification of target genes

A

Must identify target genes of receptors

Stimuli activate certain receptors => can observe mitochondrial
biogenesis, fatty acid oxidation, oxphos, etc.

35
Q

when suing ChIP- sequencing (chromatic immunoprecipitation) to identify genome wide targets, the following stops are carried out:

A

(1) Extraction of DNA with factor bound
(2) Fix factor to DNA with formaldehyde
(3) Cut into small pieces
(4) Use antibody against factor of interest, linked to beads
(5) Immunoprecipitate beads, beads often magnetic
(6) Add linkers to DNA, amplify by PCR, sequence & analyze

36
Q

what can be determined with ERR-alpha

A

the identification of metabolic pathways

allows for the generation of a map of activators and inhibitors

37
Q

cistrome

A

entire set of binding events for a given transcription factor

38
Q

ChIP sequencing identifies

A

target genes of transcription factors and their cistrome

also shows the binding spots, regulatory regions near metabolic genes that contains sites for TFs

this indicated that transcriptional regulation of metabolic genes requires the coordination between several factors

39
Q

how do Nuclear Receptors require coregulators to modulate gene expression?

A

Nuclear receptors act as activators and repressors of metabolic genes

Switch between corepressors and coactivator complexes allows TFs to act both negatively and positively on their targets in response to specific extracellular and intracellular signals

Intracellular = metabolite levels
Extracellular = hormones

Factors involved in exchange of corepressor/activator complexes as well as TF are targets of multiple extracellular and intracellular pathways

BIOC 311 (33 decks)

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