A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer (Mol Cell, 2007, 28:501-502)

報告日期: 2008/11/07
報告時間: 15:10/16:00
報告學生: 林世杰
講評老師: 曾大千
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/971107-1.pdf

A Hypoxia-Controlled Cap-Dependent to Cap-Independent Translation Switch in Breast Cancer

 

Mol Cell. 2007 Nov 9; 28(3):501-12

 

Speaker: 林世杰

Commentator: 曾大千 老師

Time:2008/11/07

Place: Room 602

 

Abstract:

 

Cells will change gene expression in response to stress or rapid changes in the environment. Translation regulation is an important step to control gene expression and it also plays an important role in cancer development and progression. Usually, translation initiation is a critical rate-limiting step to be regulated. Until now, cap-dependent and cap-independent are two kinds of processes to load translation machinery onto mRNA. Cap-dependent translation is mediated by eIF4F complex which is comprised of the 5’ cap-binding protein, eIF4E, ATP-dependent helicase eIF4A and, scaffold protein eIF4G. Moreover, cap-dependent translation can be inhibited by 4E-BP1 which disrupts eIF4F complex formation by sequestering eIF4E. 4E-BP1 is inactivated by the kinase mTOR but activated during stresses such as hypoxia when mTOR activity is decreased. However, cap-independent translation doesn’t need eIF4E but utilize an internal ribosome entry site (IRES) within the 5’untranslated region of mRNA. Therefore, IRES mRNAs can bypass translation inhibition under hypoxia condition. In this paper, the author has found that 4E-BP1 and eIF4G were overexpressed in large advanced breast cancers that expressed abundant HIF-1a. Furthermore, overexpression of 4E-BP1 decreased cap-dependent translation but increased cap-independent translation and promoted selective translation of IRES containing mRNAs under hypoxia condition. Elevated 4E-BP1 expression also promoted VEGF production, tumor angiogenesis and growth in an animal model. Therefore, the switch from cap-dependent to cap-independent mRNA translation may facilitate tumor progression even under hypoxia condition.  

 

References:

 

1. Translational control in stress and apoptosis. Nat. Rev. Mol. Cell Biol. 6, 318–327

2. Hypoxia-induciblefactor-1 alpha mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. Mol. Biol. Cell 13, 1792–1801.

3. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68, 913–963.