Gen Molekuler Carsinogesis

8/9/2019 Gen Molekuler Carsinogesis

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BODY PROTEINEnzymeReceptor

HormoneGrowth Factor Immunoglobuln

Inter!eron" Interleu#n" $yto#ne%&he'on' molecule'H(%)*H$


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+TR,-T,R PROTEIN

+IF%T PROTEIN

F,NG+I PROTEIN

PE*BENT,-%N PROTEIN

DI+TRIB,+I PROTEIN

PE*ERI-+%%N PROTEIN


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Proten' are compo'e& o! 'ubunt' calle& amno ac&'


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Bo#ma . DN% a&alah Polymer &arDe'o/yrbonucleot&e 0Ba'a" zat Gula &an 1

atau lebh gugu' Pho'phat2 3at Gula . 4D45 De'o/yrbo'e 0Rbo'e2

I#atan N4Gly#o'&a antara De'o/yrbo'e0$12 &engan Pyrm&n 0N12 atau Purn 0N62


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% G $ G % T $ T G G

T $ G $ T % G % $ $

DN% Ba'e Parng

Double hel/ con''t' o! 5complmentary 'tran&' o! DN%7


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Gene'Gene' +egment' o! DN% co&e !or proten' 0or+egment' o! DN% co&e !or proten' 0or

part' o! proten'2part' o! proten'2

Each co&ng 'egment ' calle& a geneEach co&ng 'egment ' calle& a gene One gene co&e' one proten 0or part o!2One gene co&e' one proten 0or part o!2

Gene' contan the n!ormaton whchGene' contan the n!ormaton whch

ma#e' u' what we arema#e' u' what we are


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Gene Structure

E8ery three ba'e' o! DN% ' calle& a 9co&on:

Each co&on 'pec!e' an amno ac& whch

;on together to !orm the proten

eg %TG < methonne < +T%RT

T%% < +TOP

T%G < +TOP

TG% < +TOP


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Protein Synthesis -

Transcription

Each gene co&e' !or a proten

DN% 'en'e 'tran& act' a' template

an& ' 9tran'crbe&: nto me''enger

RN% 0mrror mage o! the DN% but

,racl n'tea& o! Thymne2

DN%

mRN%

% T $ G G

, % G $ $


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Protein Synthesis- Translation

Intron' are 'plce& out o! the mRN%

mRN% lea8e' the nucleu'

In the cytopla'm" rbo'ome' attach to themRN% en'urng the correct amno ac&" !or

each co&on" ' a&&e& to a growng chan o!

amno ac&' whch !orm' the re'ultng

proten7


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%mno ac& a''embly &urng tran'laton occur' on rbo'ome'=

tRN% 'er8e' a' the crucal a&aptor molecule


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Nu#leot&a 17 Nu#leot&a 57 Nu#leot&a >7

0?:2 0>:2, $ % G

, Phe +er Tyr $y' ,

, Phe +er Tyr $y' $

, (eu +er +TOP +TOP %

, (eu +er +TOP Trp G

$ (eu Pro H' %rg ,

$ (eu Pro H' %rg $

$ (eu Pro Gln %rg %

$ (eu Pro Gln %rg G


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, $ % G

% Ile Thr %'n +er ,

% Ile Thr %'n +er $

% Ile Thr (y' %rg %

% *et Thr (y' %rg G

G @al %la %'p Gly ,

G @al %la %'p Gly $

G @al %la Glu Gly %

G @al %la Glu Gly G


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DN% RN% Proten

tran'crpton

tran'laton

Proten +ynthe''


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*utaton'*utaton'% change n the DN% 'eAuence o! the% change n the DN% 'eAuence o! the

genegene

%ll cell' acAure mutaton' a' they%ll cell' acAure mutaton' a' they&8&e&8&e

rate o! appro/ 1rate o! appro/ 14C4C

per gene per cellper gene per cell

*utaton' can alter proten pro&uct o!*utaton' can alter proten pro&uct o!

DN%" 'top gene wor#ng or act8ateDN%" 'top gene wor#ng or act8ate

genegene


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Types of Mutation

Deleton 4 DN% m''ng

In'erton 4 e/tra DN% n'erte&

E/pan'on 0%mpl!caton2 4 DN%

repeat 'ze ha' ncrea'e&

Pont *utaton 4 change n one ba'e


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Types of Mutation(in coding sequence)

%G$ TT$ G%$ $$G l& type

%G$ T$G %$$ $G Deleton%G$ TT$ $G% $$$ G In'erton

%G$ TT$ TT$ G%$ $$G E/pan'on

%T$ TT$ G%$ $GG Pont mutaton


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POINT *,T%TION

,%%

0Termnaton $o&on2

, $%

0$o&on !or +erne2

, $ ,

0$o&on !or +erne2

$$ %

0$o&on !or Prolne2


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Cancer

Cancer is a group of diseases in whichgenetically damaged cells proliferateautonomously

The genetic damage consists of mutations(eg.point mutation deletion insertion) andchromosomal rearrangements or losses

Such changes result in the loss or altered

function of molecules in!ol!ed in cell growthor proliferation.


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Genes in Cancer

Mutations could affect Protooncogenesor Tumorsuppressor genes.

Protooncogenes code for a !ariety of

growth factors growth factor receptorsen"ymes or transcription factors thatpromote cell growth and#or cell di!ision.

Mutated !ersion of Protooncogenes(er$% ras &un fos myc etc) are called'ncogenes


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Genes in Cancer

Proto-oncogenes are acti!ated to

oncogenes $y !arious mechanisms.

. Promoter insertion . *nhancer insertion

+. Chromosomal translocations

,. Gene amplification . Point mutation

O $


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Oncogen $ancer

abl Tran'locaton $*(

myc Tran'locaton Bur#tt:' (ymphoma

erb B %mpl!caton Epthelcarcnoma"

%'trocytoma"

$a Oe'ophagu' neu %mpl!caton %&eno $a 0*ammae"

O8arum" Ga'ter2

myc %mpl!caton $a4 *ammae" (ung",teru'" Oe'

N4myc %mpl!caton Neurobla'toma" $a7Paru

Int45 %mpl!caton $a4Oe'ophagu'


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poptosis

Programme& cell &eath

Intracellular machnery re'pon'ble !or

apopto'' ' calle& ca'pa'e'7

$a'pa'e' +ynthe'ze& n the cell a' nact8e precur'or calle&

proca'pa'e'

,'ually act8ate& by clea8age at a'partc ac&' byother ca'pa'e'7


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Tumor suppressor genes

Play an mportant role n tumorgene''7

In8ol8e& n the control o! abnormal cell

prol!eraton7

(o'' or nact8aton . a''ocaton wth the

&e8elopment o! malgnancy7


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Tumor suppressor genes

The ma&ority of p+ mutations (/01) in$reast cancer are missense while 012nonsense mutations deletions insertions

P+ protein (34) normally inhi$its Cd3

(Cyclin dependent 3inase) en"ymes. 5ecent e!idence indicates that other

damaged or deleted Tumorsuppressorgenes may code for en"ymes in!ol!ed in46 5epair mechanisms.

7f 46 repair mechanisms are incompletea comple8 mechanism in!ol!ing P+ leadsto programmed cell death or poptosis


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Carcinogenics

5adiant energy Chemical compounds

9iruses ( 46 !irus56 !irus deno

!irus) These act $y causing mutations or $y

introducing no!el genes into cells

:amilial conditions (Tumor suppressor

genes) '8idati!e damage to 46 increase the

mutations rate


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Photodimeri"atio

n

|A

|C

|G

|T

|T

|C

|A

|T

T|

T|

G|A|

A|C|

G|

A|

|A

|C

|G

|C

|A

|T

T|

T|

G|

C|

G|

A|

thymine

dimer

;9 light*8posure to ;9 light

can cause ad&acent

thymines to

co!alently lin3.

This results in a

distortion of the 46

molecule and$rea3s the hydrogen

$onding with the

adenine.


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Carcinogenesis (ColorectalCancer)


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Tumor metastasis

Metastasis is the most dangerous

property of tumor cells

The cell grow as secondary tumors Many changes ha!e $een documented at

the surfaces of malignant cells

Some are2 alterations in transport

property diminished adhesion loss of

certain antigens etc.

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Gen Molekuler Carsinogesis