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Pendahuluan Biologi Molekuler. DNA. DOGMA CENTRAL. RNA. Protein. Mathematical Biosciences Institute (Ohio State Univ), 2 October 2003. Dogma central Biologi Molekuler. Asam amino. fenotip. DNA Sequence (splited by genes). protein. RNA. Adapted from http://www.bioinfbook.org/. DNA.

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slide2

DNA

DOGMA CENTRAL

RNA

Protein

Mathematical Biosciences Institute (Ohio State Univ), 2 October 2003

dogma central biologi molekuler
Dogma central Biologi Molekuler

Asam amino

fenotip

DNA Sequence

(splited by genes)

protein

RNA

Adapted from http://www.bioinfbook.org/

slide4
DNA

Gula

Fosfat

Basa (A,T, C or G)

  • DNA adalah komponen yang tersusun dari dari molekul-molekul yang disebut nukleotid
  • Masing-masing nukleotid mengandung fosfat, gula dan basa nitrogen.
  • Ada empat basa: Adenine (A), Guanine (G), Cytosine (C), and Thymine (T)
dna structure
DNA: structure
  • Ikatan gula-fosfat pada nukleotid merupakan backbone dari ikatan pada DNA
  • Empat basa dari DNA dibentuk sepanjang “backbone” disebut dengan DNA sequence.
  • Dua DNA saling berikatan di antara pasangan basa
  • Dua ikatan basa yang mungkin yaitu:
  • A-T, C-G.
  • Dua untai DNA mempunyai formasi struktur double helixTwo.

Source of diagram: http://www.cs.utexas.edu/users/s2s/latest/dna1/src/page2.html

dna tersusun dalam kromosom
DNA: tersusun dalam kromosom
  • Each chromosome is essentially a package for a very long, continuous DNA double strand.

Lodish et al. Molecular Biology of the Cell (5th ed.). W.H. Freeman & Co., 2003.

dna di splid oleh gen gen
DNA: di-splid oleh gen-gen

Exon 3

Intron 2

Exon 2

promoter

Exon 1

Intron 1

gene

  • Gen merupakan bagian dari DNA yang membawa informasi untuk membentuk protein.
  • 2-3% dari DNA manusia adalah gen, gen yang tidak aktif (rest) disebut junk DNA
  • Promotor terlelak di bagian awal dari komponen gen. Promotor aktif saat gen akan bekerja.
  • Pada banyak gen euryotic, gen adalahsekuen DNA yang mempunyai kode, yang juga disebut sebagai exon. Bagian yang tidak membawa kode genetik disebut sebagai intron.
slide8
RNA
  • RNA (ribonucleic acid) adalah intermediet antara DNA dan protein.
  • RNA merupakan single strand dari asam nukleat.
  • Basa nitrogen T (Thymine) pada RNA terganti oleh U (Uracil)
  • Tidak seperti DNA, yang terlokasi di inti, RNA juga dapat ditemukan di sitoplasma.
  • Pada inti, kode gen ditranskripsikan pada RNA. Selanjutnya RNA akan keluar dari inti ke nukleus dalam sitoplasma, dimana RNA ditranslasi menjadi asam amino.

Source of diagram: http://en.wikipedia.org/wiki/RNA

another view of central dogma
Another view of central dogma

Gen diekspresikan pada 3 step:

1) Transkripsi: Sintesis RNA

2) Splicing: penghilangan intron dari RNA

3) Translasi: Sintesis Protein

transkripsi
Transkripsi
  • Transkripsi diinisiasi oleh kompleks dari faktor=faktor transkripsi yang berikatan dengan promotor.
  • An enzyme, RNA polymerase II, travels along the gradually unzipped DNA template and polymerizes nucleotides into an RNA.
  • The sequence of nucleotides on DNA template determines the sequence on RNA by following the rule of base-pair complementarity, i.e., A – U, T- A, C – G, G – C.
  • Transcription continues until entire gene is copied to RNA.

Animation

Source of diagram: http://ghs.gresham.k12.or.us/science/ps/sci/ibbio/chem/nucleic

splicing
Splicing

pre mRNA

Exon 3

Intron 2

Exon 2

Exon 1

Intron 1

mature mRNA

translation 1
Translation (1)
  • By translation, the nucleotide sequence on mRNA
  • determines the amino acid sequence by genetic code.
  • Genetic code: three base pairs of RNA (called a codon) determine one amino acid based on a fixed table.
  • Translation always starts at AUG(start codon), and ends with any of UAA, UAG, or UGA (stop codon)
translation 2
Translation (2)
  • Transfer RNAs (tRNAs): small RNA molecules. Most of the tRNAs function as carriers of amino acids and participate in protein synthesis.
  • For example, the tRNA with the anticodon CGG corresponds with the codon GCC and attaches alanine amino acid onto the peptide chain.
  • Ribosome: a complex of protein and rRNA

Animation

Source of diagram: http://www.wiley.com/legacy/college/boyer/0470003790/structure/tRNA/

summary
Summary
  • Central dogma of molecular biology
    • Three components
      • DNA
      • RNA
      • Protein
    • Three steps
      • transcription
      • splicing
      • translation
proto oncogenes encode components of growth factor signal transduction pathways
Proto-oncogenes encode components of growth factor signal transduction pathways

Components shown in yellow are known proto-oncogenes

the vegf family and its receptors
The VEGF family and its receptors

VEGF-AVEGF-BPlGF

VEGF-A

VEGF-CVEGF-D

VEGF receptor-2

VEGF receptor-1

VEGF receptor-3

– P

P–

– P

P–

– P

P–

P–

– P

P–

– P

P–

– P

Migration, permeability, DNA synthesis, survival

Angiogenesis

Lymphangiogenesis

Adapted from Ferrara N. Nat Med 2003;9:669–76

vegf signal transduction and its effects
VEGF signal transduction and its effects

VEGF

 Permeability

VEGF-C

VEGF

VEGF-D

VEGF receptor-1

VEGF receptor-2

Cation channel

VEGF receptor-3

– P

P–

– P

P–

– P

P–

P–

– P

P–

Ca2+

– P

PLC

P–

– P

IP3

PLC

Calcium release

DAG

PLC

DAG

P13K

Protein kinase C

MAPK

SAPK/ JNK

Raf-1

Protein kinase B

Proliferation

Migration

Proliferation, migration

 Permeability

Apoptosis

Survival

VEGF binding to VEGF receptor-2 activates a signalling cascade resulting in cellular effects

Shibuya M. Cell Struct Funct 2001;26:25–35

agents targeting the vegf pathway
Agents targeting theVEGF pathway

Antibodies inhibiting VEGF receptors

Soluble VEGF receptors

(VEGF-TRAP)

Antibodies inhibiting VEGF(e.g. bevacizumab)

 Permeability

VEGF

Cation channel

VEGF receptor-2

Small-molecules inhibiting VEGF receptors (TKIs)(e.g. PTK-787)

– P

P–

– P

– P

P–

P–

– P

P–

P–

P–

– P

– P

Migration, permeability, DNA synthesis, survival

Ribozymes

(Angiozyme)

Angiogenesis

Lymphangiogenesis

slide22

Growth factor

Ras

Ras

P

P

14-3-3

14-3-3

Grb2

GTP

GDP

GTP

Sos

1

2

Active Raf

P120-GAP Neurofibromin

14-3-3

3

1

1

2

2

1

2

3

3

3

MEK

P13-K

ERK1

ERK1

?

14-3-3

Rac and Rho pathway

Transcription factors etc.

DNA synthesis

Inactive Raf

Nucleus

Morphological change

Signal Transduction from Receptor to Nucleus Via RAS p21

regulators proliferation differentiation apoptosis repair
Genome :

Genes :

Cell cycle

Differentiatio

Apoptosis

Repair

Metabolism

etc

Proteome

Protein:

cyclin, CDK,CDKI

GF : GM-CSF, FGF

Bcl-2, p53, caspase

Gadd, enzym repair

dll

Regulators : proliferation, differentiation, apoptosis, repair

Transcriptome

RNA

RNA

RNA

RNA

RNA

RNA