Signal transduction

Question 1

STR superfamily

Answer 1

• steroid-thyroid-retinoid
• lipid soluble hormones
• longer time to see effects but action is longer lasting
• involved in: development, differentiation, cell to cell interaction, nutrient sensing, xenobiotic sensing

Question 2

Similarities in STR receptor superfamily

Answer 2

• DNA binding domain⇒ 2 zink fingers
• HRE ⇒ same nucleotide sequence for different receptor monomers, but spacing different
• Ligand binding domain ⇒ close to C terminal
• C terminal ⇒ associated with HSP binding and transactivators
• D region ⇒ hinge region for protein
• 2 transactivator domains ⇒ AF1 and AF2
• A/B region ⇒ coactivators, transactivators, transcription proteins

Question 3

Type 1 receptor superfamily

Answer 3

• ligand binding ⇒ results in dissociation of heat shock proteins, homo-dimerization, translocation, binding of HREs
• include androgen receptor, estrogen receptor, glucocorticoid receptor, progesterone receptor and mineraocorticoid receptor

Question 4

Mechanism of Type 1 receptor

Answer 4

hormone ⇒ NR/HSP complex in cytoplasm ⇒ NR/hormone complex + HSP ⇒ NR dimer ⇒ through nuclear pore ⇒ + coactivators ⇒ bind to HRE in DNA ⇒ mRNA ⇒ protein

Question 5

Type 2 receptor superfamily

Answer 5

• retained in nucleus regardless of ligand binding status and in addition bind as heater-dimers to DNA
• often complexed with corepressor proteins (absence of ligand)
• ligand binding ⇒ dissociation of corepressor and recruitment of coactivator protein + RNA polymerase
• no HSP association
• include retinoic acid receptor, retinoic X receptor and thyroid hormone receptor

Question 6

Special features of transcription factors of receptors

Answer 6

• Alpha-helices
• helix-turn- helix
• helix-loop-helix
• leucine zipper
• Zn finger

Question 7

Zinc finger

Answer 7

small protein structural motif that is characterized by the coordination of one or more zinc ions in order to stabilize the fold

Question 8

Steroid type receptor

Answer 8

• located in cytoplasm + associated with HSP until ligand bind ⇒ translocate
• long A/B domain
• do not bind to HRE unless ligand binds
• display repressor effects
  must dimerize in order to bind to HRE
• agonist/antagonist binding site is different

Question 9

Thyroid type receptor

Answer 9

• short A/B domain
• no heat shock protein association
• bind to HRE without ligand + can bind as monomers
• complex with corepressor proteins

Question 10

Hormone resistance syndromes and disease association

Answer 10

• Glucocorticoid resistance ⇒ hypercortisolism without Cushing symptoms
• Mineralocorticoid resistance ⇒ pseudohypoaldosteronism
• Androgen resistance ⇒ testicularis feminisatio
• D-vitamin resistance ⇒ rickets
• ER overproduction ⇒ breast cancer
• AR overprod. ⇒ prostate cancer
• GR detection ⇒ leukemias, lymphoid tumors, uterus tumors

Question 11

Antiestrogens

Answer 11

• e.g. Tamoxifen
• do not dissociate + cause inhibition of dimer formation
• compete for hormone binding site
• bind to receptors, enter cell but do not bind coactivators ⇒ genetic translation not affected

Question 12

Hypoxia inducible factors (HIFs)

Answer 12

• transcription factors, respond to changes in available oxygen in cellular environment
• HIF-1 ⇒ heterodimer of alpha and beta subunit(ARNT)⇒ upregulates genes to promote survival in low-oxygen conditions
• HIF signaling cascade mediates effect of hypoxia
• vital to development

Question 13

Hypoxia

Answer 13

• keeps cells from differentiating
• promotes formation of blood vessels
• important for formation of vascular system in embryos and cancer tumors
• promotes migration of keratinocytes + restoration of epithelium

Question 14

HIF-1

Answer 14

• part of basic helix-loop-helix protein eukaryote transcription factor super gene family
• HIF1a/HIF1b heterodimer in every tissue
• HIF-1a inducible oxygen sensitivie
• HIF-1b oxygen insensitive
• HIF-1a increased in hypoxia within minutes
• HIF-1a increased in malignant tumors

Question 15

Receptor Tyrosine kinase

Answer 15

• high-affinity cell surface receptors for many polypeptide growth factors, cytokines and hormones
• can activate G protein linked pathway
• vital in differentiation and proliferation of many cell types
• ligand binds⇒ dimerisation ⇒ autophosphorylation⇒ intracellular domain activate signal transduction pathway

Question 16

Types of Protein Tyrosine Kinases

Answer 16

1. Plasma membrane receptors- receptor tyrosine kinase ⇒ dimer formation, autophosphorylation
2. Cytoplasmic tyrosine kinases

Question 17

SH2 domain

Answer 17

• structurally conserved protein domain contained within Src oncoprotein and many other intracellular signal-transducing proteins
• allow proteins to dock to phosphorylated tyrosine residues on other proteins
• commonly found in adapter proteins
• function: recognize phosphorylated state of tyrosine residues

Question 18

Insulin receptor

Answer 18

• heterotetramer 2a,2B
• insulin binding ⇒ change in structure ⇒ activates B-subunit TK activity ⇒ phosphorylates Tyr residues on cytoplasmic domains + IRS
  ⇒⇒
  1. Phosphatidylinositol 3 hydroxy kinase ⇒ PIP2, PIP3
  2. Growth factor receptor- bound protein 2
  3. Son of Sevenless (SoS) ⇒ Ras signaling pathway
  4. Activation of PI-PLCy

Question 19

IFNy receptor

Answer 19

• type 2 interferon is a cytokine critical for innate and adaptive immunity
• activator of macrophages
• produced by natural killer cells and natural killer T cells, CD4 Th1 and CD8 cytotoxic T lymphocytes
• IFNy binds ⇒ recruitment of JAK tyrosine kinase ⇒ phosphorylate STAT ⇒ dimerise + translocate⇒ gene transcription

Question 20

Tumor Necrosis factor TNF

Answer 20

• cytokine involved in systemic inflammation + stimulate acute phase reaction
• produced by macrophages + CD4 lymphocytes, NK cells, neurons
• role: regulate immune cells
• endogenous pyrogen ⇒ induce fever, apoptotic cell death, sepsis, cachexia, inflammation, inhibit tumorigenesis + viral replication
• binding causes activation of TRAF2⇒ IkB ubiquinated + degraded, NFkB translocate ⇒ target genes

Question 21

Gs stimulatory siganls

Answer 21

• glucagon, ACTH, B-adrenergic agonist
• parathormone, LH, TSH, dopamine
• vasopressin, histamine

Question 22

Proteins phosphorylated by PKA

Answer 22

• glucogen synthase -
• HSL +
• L-pyruvate kinase -
• Tyrosine hydroxylase +
• Fructose 2,6 bisphosphate synthase liver -
• phosphorylase kinase +
• myosin light chain kinase -
• CREB cAMP response element binding protein
• Ca2+ pump heart +
• phosphoprotein phosphatase 1 -