TELOMERE

Telomere-relatedAgeing and Cancer

20090400 김소은20090410 김 준

Contents

•DISCOVERY

•AGING

•CANCER

•THERAPY

Telomere

• Telomere 는 chromosome 의 끝부분에 있다 .• Telomere 가 없는 chromosome 은 sticky 하다 .

The Nobel Prize in Physiology or Medicine 2009

End Replication Problem

• Linear DNA 는 복제 시 끝부분이 점점 짧아져야 한다 .• 그러나 실제로는 길이가 거의 유지되며 genetic information 의 손실이 없다 .

The Nobel Prize in Physiology or Medicine 2009

Telomere Discovery

• Elizabeth Blackburn 은 Tetrahynema에서 minichromosome 을 분리시켰다 .• Minichromosome 에는 20~70 회 반복되는 CCCCAA sequence 가 있었다 .

The Nobel Prize in Physiology or Medicine 2009

Function of Telomere

• Artificial linear DNA 를 yeast 에 그냥 넣을 때는 모두 분해되었다 .• 그러나 여기에 Tetrahymena의 telomere 를 붙이자 , 분해되지 않았다 .

The Nobel Prize in Physiology or Medicine 2009

Telomerase Discovery

• Telomere, nucleotides, Tetrahymena extract 를 섞자 telomere 가 길어졌다 .• Telomere 의 길이를 늘리는 enzyme 이 존재할 것이다 . The Nobel Prize in Physiology or Medicine 2009

Telomerase

• Telomerase 는 telomere 와 sequence 의 RNA template 를 지닌 reverse-tran-scriptase 이다 .

The Nobel Prize in Physiology or Medicine 2009

Telomere Structure

• Telomere 에는 telomere maintenance 에 중요한 여러 protein 이 binding 하여 structure 를 이룬다 .

Blasco, 2005

Discussion

“ 진화적으로” telomere 와 telomerase 는어떻게 생겨났을까 ?

The Nobel Prize in Physiology or Medicine 2009

Contents

•DISCOVERY

•AGING

•CANCER

•THERAPY

Aging

Werner syndromes

• Telomerase 가 없는 somatic cell 의 telomere 는 나이에 따라 점차 짧아진다 .• Premature syndrome 은 short telomere 의 phenotype 을 보인다 .

http://www.wernersyndrome.org/ Blasco, 2005

Mitotic Clock Theory

Blackburn, 2000

Fig. 2. Mitotic clock theory

• Telomere 가 짧아지는 것은 cell 의 proliferation 을 제한한다 .• Telomere shortening 은 senescence, cancer 와 관련이 있다 .

Fusion

• Telomere 길이가 아주 짧아지면 chromosome fusion 이 일어난다 .• Premature syndrome 에서도 이를 확인할 수 있다 .

Du, 2004

Cell Death

Du, 2004

• Telomere 가 짧아지면 세포가 죽게 된다 .

Telomere Length

Herrmann et al., 2001

• 가장 짧은 telomere 가 fusion 을 일으키며 , fusion 은 다시 apoptosis 를 일으킨다 .• Telomerase 는 가장 짧은 telomere 에 대한 preference 가 있다 .

Chromosome Fusion

Herrmann et al., 2001

• Telomere 가 없는 것은 chromosome fusion 과 아주 높은 상관관계를 보인다 .

Contents

•DISCOVERY

•AGING

•CANCER

•THERAPY

Cancer

Telomere dysfunctionAnd Telomerase reintroduction

• Chromosome instability 는 telomerase 가 다시 작동할 수 있게 한다 .

Blasco, 2005

Tumor

• 짧은 telomere 와 telomerase 결핍은 tumor 를 억제한다 .

González-Suárez et al., 2000

Epigenetic Regulation

• Telomere 의 epigenetic regulation 은 telomerase 의 access 를 조절한다 .• Regulation 에 이상이 생기면 telomere 가 길어지고 , 이는 cancer 를 유발한다 .

Blasco, 2005

Blasco, 2005

Contents

•DISCOVERY

•AGING

•CANCER

•THERAPY

Telomere Measurement

http://www.scientificamerican.com/article.cfm?id=my-what-long-telomeres-you-have

Cancer Therapy

Mutant-Template Telomerase RNA(MT-hTer) and Anti-telomerase short-in-terfering RNA caused p53-independent cell growth inhibition and apopto-sis, in telomerase-positive precancerous or cancer cells but not in telom-erase-negative cells.

Co-expression of MT-hTer and siRNA synergistically killed cancer cells.

smaller andless vascularized tumors in mice than wild-typehuman telom-erase RNA con-trols.

Li, 2004

Delivery of siRNA targeting hTERT

biodegradable polyethylenimine containing multiple disulfide bonds (SS-PEI) was successfully applied as a potent non-viral carrier for intracellular delivery of the hTERT siRNA in vitro and in vivo.

Xiaa, 2011

Drugs and Vaccines in Clinical Trial

Telomerase Inhibitor Drug, Imetelstat(GRN163L)

Telomerase Cancer Vaccine, GRNVAC1

Oligonucleotides(target template region of telom-erase)In phase 2 clinical trial

Peptide vaccine, GV1001 http://www.kael.co.kr/

02_product/01_bio_01.asp

http://www.geron.com/products/productinformation/cancerdrug.aspx

http://www.geron.com/products/productinformation/cancervaccine.aspx

Anti-ageing Pill

TA-65 is a naturally occurring single molecule found in the ancient Chinese herb Astragalus.TA-65 is a telomerase activator, which turns on the hTERT gene.

drdavesbest.com

Mechanism of GRN163L

GRN163L is telomerase active site inhibitor.

Harley, 2008

Discussion

González-Suárez et al., 2000

DePinho, 2000

Telomerase activity 를 조절하는 의약품은Cancer 발생에 어떤 영향을 미칠까 ?

Discussion

Cell 의 senescence 와 우리가 흔히 생각하는 “ aging” 은 어떤 관계가 있을까 ?

Chromosome 마다 telomere 길이가 왜 다른 걸까 ?

세포의 telomerase activity 를 어떻게 측정할까 ?

다른 therapy 방법은 어떤 것이 있을까 ?

Reference

http://www.wernersyndrome.org/ The Nobel Prize in Physiology or Medicine 2009 Maria A. Blasco (2005), Telomeres and Human Disease: Ageing, Cancer and Beyond, Nature reviews

genetics, voloume 6, August 2005, 611-622 Xiaobing Du, Johnny Shen, Nishan Kugan, Emma E. Furth, David B. Lombard, Catherine Cheung,

Sally Pak, Guangbin Luo, Robert J. Pignolo, Ronald A. DePinho, Leonard Guarente, and F. Brad Johnson (2004), Telomere Shortening Exposes Functions for the Mouse Werner and Bloom Syn-drome Genes, Molecular and cellular Biology, October 2004, 24(19), 8437–8446

Eva González-Suárez, Enrique Samper, Juana M. Flores & María A. Blasco (2000), Telomerase-defi-cient Mice with Short Telomeres are Resistant to Skin Tumorigenesis, Nature genetics, volume 26, September 2000, 114-117

Ronald A. DePinho (2000), The Age of Cancer, NATURE, Volume 408, 9 November 2000, 248-254 Wei Xiaa,Peijun Wanga,Chao Linb,Zhuoquan Lib,Xiaolong Gaoa,Guoliang Wanga,Xiaohu Zhaoa

(2011), Bioreducible polyethylenimine-delivered siRNA targeting human telomerase reverse transcrip-tase inhibits HepG2 cell growth in vitro and in vivo,Journal of Controlled Release,doi:10.1016/j.jcon-rel.2011.10.011

Shang Li, Jonathan E. Rosenberg 1, Annemarie A. Donjacour, Inna L. Botchkina, Yun Kit Hom, Gerald R. Cunha, and Elizabeth H. Blackburn(2004),Rapid Inhibition of Cancer Cell Growth Induced by Lentiviral Delivery and Expression of Mutant-Template Telomerase RNA and Anti-telomerase Short-In-terfering RNA,Cancer Res,July 15

Calvin B. Harley (2008), Telomerase and cancer therapeutics, NATURE REVIEWS|CANCER, Volume 8 , March2008, 167-179