Induction of the p53 Tumor Suppressor in Cancer Cells through Inhibition of Cap-Dependent Translation

Molecular and Cellular Biology
Benjamin R HarrisDa-Qing Yang

Abstract

The p53 tumor suppressor plays a critical role in protecting normal cells from malignant transformation. Development of small molecules to reactivate p53 in cancer cells has been an area of intense research. We previously identified an internal ribosomal entry site (IRES) within the 5' untranslated region of p53 mRNA that mediates translation of the p53 mRNA independent of cap-dependent translation. Our results also show that in response to DNA damage, cells switch from cap-dependent translation to cap-independent translation of p53 mRNA. In the present study, we discovered a specific inhibitor of cap-dependent translation, 4EGI-1, that is capable of inducing the accumulation of p53 in cancer cells retaining wild-type p53. Our results show that 4EGI-1 causes an increase in p53 IRES activity, leading to increased translation of p53 mRNA. We also observed that 4EGI-1 induces cancer cell apoptosis in a p53-dependent manner. Furthermore, 4EGI-1 induces p53 in cancer cells without causing DNA double-strand breaks. In conclusion, we discovered a mechanistic link between inhibition of cap-dependent translation and enhanced p53 accumulation. This leads to apoptosis of cancer cells without causing collateral damage to normal cells, thus...Continue Reading

References

Sep 15, 1995·The EMBO Journal·J MosnerW Deppert
Feb 1, 1997·Seminars in Cancer Biology·D MacGrogan, R Bookstein
Aug 5, 2000·Medical and Pediatric Oncology·A C TaylorL C Harris
Dec 1, 2000·Nature·B VogelsteinA J Levine
Jul 11, 2001·Genes & Development·C U Hellen, P Sarnow
Mar 7, 2002·Breast Cancer Research : BCR·Milena GascoTim Crook
Apr 30, 2003·Cell Death and Differentiation·J D Weber, G P Zambetti
Jun 25, 2003·Proceedings of the National Academy of Sciences of the United States of America·Krystyna Mazan-MamczarzMyriam Gorospe
Oct 1, 2003·Molecular and Cellular Biology·Stefanie GalbánMyriam Gorospe
Oct 1, 2003·The Prostate·Adrie van BokhovenM Scott Lucia
Oct 31, 2003·Cancer Cell·John R JeffersGerard P Zambetti
Apr 20, 2004·Oncogene·Arrigo De Benedetti, Jeremy R Graff
Apr 2, 2005·Nature Reviews. Molecular Cell Biology·Martin Holcik, Nahum Sonenberg
May 4, 2005·Biochemical and Biophysical Research Communications·Jian Yu, Lin Zhang
Feb 27, 2007·Oncogene·H F Horn, K H Vousden
Jun 15, 2007·Journal of Zhejiang University. Science. B·Estelle SchmittRichard Bertrand
Sep 6, 2007·The Journal of Clinical Investigation·Jeremy R GraffEric G Marcusson
May 5, 2009·Cell·Karen H Vousden, Carol Prives
Nov 26, 2009·Journal of Agricultural and Food Chemistry·Jia-Ni LinTzong-Der Way
Nov 26, 2009·Nature Reviews. Cancer·Christopher J BrownDavid P Lane
Jan 26, 2011·Annals of the New York Academy of Sciences·Hung-Yun LinPaul J Davis
Oct 22, 2011·Cell Death and Differentiation·S P GarrisonG P Zambetti
Jan 14, 2012·Expert Opinion on Therapeutic Targets·Alexander H Stegh
Apr 13, 2012·Medicinal Research Reviews·Yan JiaCarston R Wagner
Sep 1, 2012·Cell Death and Differentiation·D-Y KimK-T Kim
Sep 1, 2012·Oncotarget·Limo ChenJose A Halperin
May 2, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Shaun WillimottSimon D Wagner
Nov 23, 2013·Cancer Letters·Tom Van MaerkenJo Vandesompele
Jul 23, 2014·Proceedings of the National Academy of Sciences of the United States of America·Evangelos PapadopoulosGerhard Wagner
Jan 17, 2015·Cancer Research·Jerry PelletierNahum Sonenberg
Feb 28, 2015·Cell Death and Differentiation·D KhanS Das
Mar 3, 2015·Oncotarget·Anne Y SaikiJonathan D Oliner
Aug 15, 2015·BioMed Research International·Marie-Jo HalabyDa-Qing Yang

❮ Previous
Next ❯

Citations

Aug 1, 2020·International Journal of Molecular Sciences·Hsiuying Wang
Aug 14, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Mark D TurnerAlan R Hipkiss

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.