Pendahuluan Biologi Molekuler DOGMA CENTRAL DNA RNA Protein
Pendahuluan Biologi Molekuler
DOGMA CENTRAL DNA RNA Protein Mathematical Biosciences Institute (Ohio State Univ), 2 October 2003
Dogma central Biologi Molekuler DNA Sequence (splited by genes) RNA Asam amino Adapted from http: //www. bioinfbook. org/ protein fenotip
DNA Gula Fosfat Basa (A, T, C or G) • DNA adalah komponen yang tersusun 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 • 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 helix. Two. Source of diagram: http: //www. cs. utexas. edu/users/s 2 s/latest/dna 1/src/page 2. html
DNA: tersusun dalam kromosom l Each chromosome is essentially a package for a very long, continuous DNA double strand. Lodish et al. Molecular Biology of the Cell (5 th ed. ). W. H. Freeman & Co. , 2003.
DNA: di-splid oleh gen-gen promoter Exon 1 Intron 1 Exon 2 Intron 2 Exon 3 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.
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 Gen diekspresikan pada 3 step: 1) Transkripsi: Sintesis RNA 2) Splicing: penghilangan intron dari RNA 3) Translasi: Sintesis Protein
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. k 12. or. us/science/ps/sci/ibbio/chem/nucleic
Splicing pre m. RNA Exon 1 Intron 1 Exon 2 mature m. RNA Intron 2 Exon 3
Translation (1) • By translation, the nucleotide sequence on m. RNA 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) l Transfer RNAs (t. RNAs): small RNA molecules. Most of the t. RNAs function as carriers of amino acids and participate in protein synthesis. l For example, the t. RNA with the anticodon CGG corresponds with the codon GCC and attaches alanine amino acid onto the peptide chain. l Ribosome: a complex of protein and r. RNA Animation Source of diagram: http: //www. wiley. com/legacy/college/boyer/0470003790/structure/t. RNA/
Summary l Central dogma of molecular biology l Three components l DNA l RNA l Protein l Three steps l transcription l splicing l translation
Cell – cell communication
Protooncogenes encode components of growth factor signal transduction pathways Components shown in yellow are known protooncogenes
The VEGF family and its receptors VEGF-A VEGF-B Pl. GF VEGF-A VEGF receptor-2 VEGF receptor-1 P– P– –P –P VEGF-C VEGF-D VEGF receptor-3 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 Permeability VEGF-C VEGF-D VEGF receptor-1 VEGF receptor-2 –P –P P– P– VEGF receptor-3 P– P– Ca 2+ PLC Cation channel IP 3 Calcium release DAG –P –P PLC P 13 K Protein kinase C Raf-1 MAPK Proliferation, migration Permeability SAPK/ JNK Apoptosis Survival Protein kinase B Proliferation Migration 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 Antibodies inhibiting VEGF receptors Soluble VEGF receptors (VEGF-TRAP) Antibodies inhibiting VEGF (e. g. bevacizumab) Permeability VEGF Cation channel VEGF receptor-2 P– P– –P –P Small-molecules inhibiting VEGF receptors (TKIs) (e. g. PTK-787) P– P– –P –P P– P– Migration, permeability, DNA synthesis, survival Ribozymes (Angiozyme) Angiogenesis Lymphangiogenesis –P –P
Signal Transduction from Receptor to Nucleus Via RAS p 21 Growth factor P Ras P Grb 2 GTP GDP Sos P 120 -GAP 14 -3 -3 Neurofibromin 1 2 14 -3 -3 1 2 3 3 Active Raf 3 MEK P 13 -K 14 -3 -3 1 Rac and Rho pathway 2 ERK 1 3 Inactive Raf Transcription factors etc. Nucleus Morphological change ? DNA synthesis
Regulators : proliferation, differentiation, apoptosis, repair l l Genome : Genes : l l l Cell cycle Differentiatio Apoptosis Repair Metabolism etc Transcriptome l l Proteome Protein: RNA l RNA RNA l l l cyclin, CDKI GF : GM-CSF, FGF Bcl-2, p 53, caspase Gadd, enzym repair dll
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