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MBBS II ERS > L27 – Molecular Mechanisms of Growth Control > Flashcards

L27 – Molecular Mechanisms of Growth Control Flashcards

1
Q

5 mechanisms that influence cell growth?

A
  • Contact inhibition: space between cells**
  • Supply and demand: energy
  • Cell division counting: Number of cells**
  • Cell mass sensor: Size of cells**
  • Negative cellular growth regulator: e.g. tuberin (TSC2)
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2
Q

What are the hormones responsible for post-natal growth? exams

A
  1. Growth hormone
  2. Thyroid hormone
  3. Sex hormones (estrogen, testosterone)
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3
Q

List some factors which influence the rate of cell apoptosis/ cell number?

A

Anti-apoptotic proteins (Bcl-2,) Pro-apoptotic proteins (Bad, Bax)

Mitogens (EGF, PDGF) > DNA replication

Survival factors (IL3)

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4
Q

Describe the effects of Growth hormone on bones and liver?

A

Bone: bind to GH-receptor on gowth plate = elongation o bone

Liver: Cause IGF-1 secretion***

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5
Q

Outline the fucntions of IGF-1?

A
  • Negative feedback inhibition on pituitary gland > stop GH secretion
  • Act on growth plate of bones: Increase growth, proliferation, inhibit apoptosis
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6
Q

List 3 tests for growth hormone function?

A

Growth hormone provocation tests:

1) Insulin tolerance test: cause hypoglycemia&raquo_space; stress response to ↑ GH
2) Glucagon stimulation test: releases GH
3) Clonidine stimulation test: α-2 adrenergic receptor agonist antihypertensive lowers BP&raquo_space; stimulates pituitary to secrete GH

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7
Q

Factors/hormones that influence growth hormone/ GH-IGF1 AXIS function? exam

A

Major:
• GH-releasing hormone (GHRH): stimulatory effects
• Ghrelin: stimulatory effects
• Somatostatin: inhibition of somatotroph cell function

Others:
 Nutrition
 Negative feedback  
 Other hormones: sex steroids, glucocorticoids 
 Epigenetic
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8
Q

Why is GH spot check inaccurate for Dx of GH problems? Treatment for growth hormone deficiency?

A

normal GH secretion: pulsatile (4 to 6 pulses per 24 hours)= Too variable to test directly

Somatotropin

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9
Q

Which disease must be excluded in children with growth problems? What tests should be given?

A

Pituitary lesions (e.g. Craniopharyngioma): causes Growth hormone defect with multiple pituitary hormone deficiency (MPHD), rarely isolated GHD

Clinical assessment + biochem tests (e.g. Serum IGF-1 test) + radiological evaluation

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10
Q

Pathogenesis of Laron dwarfism?

A

Autosomal recessive mutation affecting GH receptor gene

Decreased IGF-1 levels despite increased GH secretion

> > Reduce growth, metabolism, increased apoptosis of cells

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11
Q

Describe the intracellular signalling of growth hormones?

A

GH binds to GHR

> > Activate JAK2 to self-phosphorylate
dimerize 2 STAT proteins by phosphorylation
Dimer enters nucleus for transcription of target genes
Form IGF1/IGFBP3/ALS ternary complex**

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12
Q

Which type of GH mutation causes Immunodeficiency, recurrent chest infections?

A

Intra-cellular GH signaling pathway mutation:

STAT5b mutation

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13
Q

Effects of IGF-1 synthesis mutation? List some symptoms?

A

• Pre- + post-natal growth failure

  • Severe intrauterine growth retardation
  • Sensorineural deafness
  • Severe psychomotor retardation
  • Microcephaly
  • Mild dysmorphic features
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14
Q

Effect of mutation causing defective growth factor transport?

A

Acid labile subunit (ALS) deficiency

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15
Q

Effects of IGF1 insensitivity?

A

Severe pre- + post-natal growth failure

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16
Q

IGF-1 and GH can both be detected in the serum. T or F?

A

True, can order test for both

17
Q

Downstream intracellular signalling of IGF-1?

A

IGF1 activate kinase receptor

> > recruit PI3K to receptor complex

> > Phosphorylate PIP2

> > Activate PDK1 and Akt:

  • Inhibit BAD, Forkhead = cell survival
  • Inhibits GSK3 = metabolism
18
Q

Which intracellular signalling pathway is most commonly*** mutated in cancer?

A

PI3K/AKT/mTOR pathway

Cause a spectrum of overgrowth syndromes

19
Q

Which types of cancers are most commonly associated with PI3K/AKT/mTOR pathway?

A

Breast, Ovarian, GIT

+ many others: e.g. HCC, RCC, THyroid, Glioblastoma…etc

20
Q

List 2 overgrowth disorders caused by defective PI3K/AKT/mTOR pathway?

A
  1. Congenital segmental overgrowth
  2. Tuberous sclerosis: Mutant TSC1, TSC2 (tumour suppressors) decrease inhibition on mTOR&raquo_space; Non-cancerous tumors in brain and other vital organ
21
Q

List some symptoms of Tuberous Sclerosis? Clinical outcome? Inheritance pattern?

A 
 Ashleaf spots 
 Lung hamartomas 
 Epilepsy 
 Angiomyolipoma in kidney 
 Facial angiofibroma

Auto. Dominant
Non-cancerous tumours in brain and vital organs

22
Q

Treatment of Tuberous Sclerosis?

A

rapamycin

suppresses mTOR = suppress cell proliferation

23
Q

3 pathways for transmission of PI3K signal?

A
  1. Akt phosphorylate TSC2&raquo_space; remove inhibition on mTOR
  2. Akt directly phosphorylate/ activate mTOR
    (3. PDK1 phosphorylate P70-S6K < effector of mTOR)
24
Q

Define the effects of Fibroblast growth factor on bones?

A

Act on the Resting and Hypertrophic regions of Growth plate in bones

> > suppress Bone morphogenetic protein (BMP)
suppress bone growth

25
Q

Summarize functions of FGF?

A

mainly act on Chondrocytes, Regulate:

  • developing axial and craniofacial skeleton
  • intramembranous ossification of cranial bones
  • Tissue repair in adults
26
Q

What type of receptors is FGF- receptors? Downstream signalling pathways?

A

Tyrosine kinase receptors

  • RAS/MAP kinase
  • PI3/AKT
  • PLCg
27
Q

List 2 conditions resulting from aberrant FGF-FGFR signalling?

A

achondroplasia/ Hypochondroplasia

craniosynostosis

28
Q

Describe FGF- FGFR complex formation and signalling?

A

2 FGF, 2 heparin sulpahte bind to 2 FGFR > dimerization and activate:

RAS/MAP kinase pathway = cell proliferation and differentiation

PI3/AKT pathway = Regulates cell survival

PLCg pathway = cell morphology, migration, and adhesion

29
Q

Pathogenesis of Achondroplasia?

A

FGFR3 gain of function mutation on proliferating chondrocytes

> > BLOCK chondrocyte proliferation and maturation**
inhibition of endochondral ossification

> > disproportionate short stature, lordosis, narrow thorax, long trunks

30
Q

List one growth factor that acts against FGFR3?

A

C-type natriuretic peptide (CNP)&raquo_space; Inhibit MAPK signaling pathway downstream of FGFR3

Produced within cartilage growth plate as a bone growth promoter

31
Q

List 3 drugs that act against FGFR3?

A
  • Statin = Accelerate FGFR3 degradation on chondrocytes
  • Meclozine (anti-emetic) = chondrocyte proliferation and differentiation
  • C-type natriuretic peptide = inhibit FGFR3 action

MBBS II ERS (37 decks)

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