Úvod

do molekulárnej medicíny

Doc. MUDr. Ing. RNDr. Peter Celec, DrSc., MPH

petercelec@gmail.com

www.imbm.sk

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Linus Carl Pauling

(1901 – 1994)

Nobel prize

1954 – Chemistry

1962 – Peace

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„Life is a relationship between molecules, not a

property of any one molecule. So is therefore

disease, which endangers life. While there are

molecular diseases, there are no diseased

molecules.“

Linus C. Pauling, 1962

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Francis Crick

(1916 – 2004)

Nobel prize

1962 – Physiology or medicine

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James Watson

(1928 – )

Nobel prize

1962 – Physiology or medicine

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Genome (DNA)

Transcriptome (RNA)

Proteome (protein)

Metabolome (pathways)

Systems biology

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DNA is information!!!

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Information processing

Communication

Intercellular

Intracellular

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Signalling pathways

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Reception

Ligands

Hydrophilic

Small molecules

Larges proteins

Hydrophobic

Steroids

Thyroxine

Retinoids

Receptors

G-protein coupled

Tyrosine kinases

Ion channels

Intracellular

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Signalling pathways

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G-protein coupled

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Phosphate

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MAP kinases

GEF – Guanine Nucleotide Exchange Factor

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Second messangers

cAMP

cGMP

IP3

DAG

Ca++

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Gene

„The gene is by far the most sophisticated

program around.“

Bill Gates

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Nobel Prize in Chemistry 2006

Roger D. Kornberg

USA

Stanford University

b. 1947

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"for his studies of the molecular basis of

eukaryotic transcription"

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Gene expression regulation

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Jak – Janus (Roman god of gates and doors) Kinase

Jak – Just Another Kinase

STAT – Signal Transducers and Activators of Transcription

APS – Adaptor protein with Pleckstrin homology and Src homology 2 domains

C-Cbl - Casitas B-lineage Lymphoma

EPO – Erythropoietin

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GR – Glucocorticoid Receptor

FKBP – FK506 (tacrolimus)-Binding Protein

HSP – Heat Shock Protein

GRE – Glucocorticoid Response Element

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TGACTCA

c-Fos – FBJ (Finkel MP, Biskis BO, Jinkins PB) OsteoSarcoma virus

AP-1 – Activator Protein 1

AP-1

FAP

FAP – c-Fos AP-1 binding site

IP-1 – Inhibitory Protein 1

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NFκB

FasL – Fas Ligand

TRAF – TNFα Receptor Associated Factor

NIK – NFκB Inducing Kinase

CBP – CREB Binding Protein

NFkB

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...but...

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Signalling pathways

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Responses???

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Cell death

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Apoptosis

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Autophagy

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Autophagy

Microautophagy

Macroautophagy

Chaperone-mediated

Pexophagy

Mitophagy

Xenophagy

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Oxygen sensingHIF – Hypoxia Inducible Factor

IGFR – Insulin like Growth Factor Receptor

EGFR – Epidermal Growth Factor Receptor

HER2 – Human Epidermal growth factor Receptor 2

PI3K – PhosphatidylInositol-3-Kinase

AKT – serine/threonine protein kinase B

FRAP – FKBP rapamycin associated protein

PH – Prolin Hydroxylases

HDAC – histone deacetylase

VHL – von Hippel-Lindau tumour suppressor protein

FIH – factor inhibiting HIF-1α

B – elongin B

C – elongin C

C2 – cullin 2

HRE – hypoxia response element

GLUT – glucose transporter

ARNT – Aryl hydrocarbon Receptor Nuclear Translocator

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Oxygen sensingHIF – Hypoxia Inducible Factor

IGFR – Insulin like Growth Factor Receptor

EGFR – Epidermal Growth Factor Receptor

HER2 – Human Epidermal growth factor Receptor 2

PI3K – PhosphatidylInositol-3-Kinase

AKT – serine/threonine protein kinase B

FRAP – FKBP rapamycin associated protein

PH – Prolin Hydroxylases

HDAC – histone deacetylase

VHL – von Hippel-Lindau tumour suppressor protein

FIH – factor inhibiting HIF-1α

B – elongin B

C – elongin C

C2 – cullin 2

HRE – hypoxia response element

GLUT – glucose transporter

ARNT – Aryl hydrocarbon Receptor Nuclear Translocator

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Angiogenesis

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Napoleone Ferrara

Genentech

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Aaron

Ciechanover

Avram

Hershko

Irwin

Rose

1/3 of the prize

Israel

1/3 of the prize

Israel

1/3 of the prize

USA

Technion – Israel

Instutute of

Technology

Haifa, Israel

Technion – Israel

Institute of

Technology

Haifa, Israel

University of California

Irvine, CA, USA

b. 1947 b. 1937

(Karcag, Hungary)

b. 1926

The Nobel Prize in Chemistry 2004"for the discovery of ubiquitin-mediated

protein degradation"

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Ub

E1

Ub

E2

Ub

E3

Ub

26S proteasome degradation

Target

UbUbUb

Ubiquitin pathway

Ubi-activating E Ubi-conjugating E Ubi-ligase

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Ub

ATP AMP + PPi

E1E1C

E2C

E2

E3C

E3

Protein K

Protein

E3

E3

Protein K

Protein K

E2

E3Protein K

E3

E2C

Ub

Protein

AMP + PPi

Protein K

Proteosynthesis

Antigen presentation

H

A

B

C1

C2

D

E

Ub

Protein

ATP

Protein

Protein

I

F

G

J

Nobel Prize in Physiology or Medicine 2007

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Mario R. Capecchi Sir Martin J. Evans Oliver Smithies

1/3 of the prize 1/3 of the prize 1/3 of the prize

USA United Kingdom USA

University of Utah

Salt Lake City, UT,

USA; Howard

Hughes Medical

Institute

Cardiff University

Cardiff, United

Kingdom

University of North

Carolina at Chapel

Hill

Chapel Hill, NC,

USA

b. 1937

(in Italy)b. 1941

b. 1925

(in United Kingdom)

"for their discoveries of

principles for introducing

specific gene modifications

in mice by the use of

embryonic stem cells"

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Individualized medicine

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Dennis Lo

Fetus is similar to a tumor

Non-invasive prenatal diagnosis

Sex

RhD

Aneuploidies

Fetal genome52

Synthetic biology

Production of synthetic microorganisms

Technology (detoxification, production,

therapy?)

Genome editing

Feng Zhang

Clustered Regularly Interspaced Short

Palindromic Repeats (CRISPR)

CRISPR associated (Cas) nuclease, Cas9

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Shinya Yamanaka(1962 - )

iPSC

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Shinya Yamanaka

Kyoto University

iPS

Reprogramming of differentiated

cells

Pluripotency

No immune response

Without retroviral vectors

Without oncogenes

Parabiosis

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Prevention of wrong advices

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petercelec@gmail.com

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