Effects of 4E-BP1 expression on hypoxic cell cycle inhibition and tumor cell proliferation and survival.

Cancer Biology & Therapy
Bryan C BarnhartM Celeste Simon

Abstract

Elevated activity of the eIF4F complex, which controls initiation of cap-dependent mRNA translation, has been linked to cancer progression. eIF4E recruitment to eIF4F is the rate limiting step of complex assembly and is regulated by eIF4E-Binding Proteins (4E-BPs). When stimulated, the mammalian Target of Rapamycin complex 1 (mTORC1) phosphorylates 4E-BP1, which then releases eIF4E. Hypoxia inhibits mTORC1 activity and therefore cap-dependent protein synthesis. To establish a novel genetic test of the role of eIF4F activity in regulating cell division and viability within hypoxic tumor microenvironments, we generated shRNA mediated 4E-BP1 knock-down in Rh30 rhabdomyosarcoma cells. 4E-BP1 knock-down relieved hypoxia-mediated inhibition of cycle progression in vitro and was correlated with increased expression of cyclin D1 and c-Myc. Xenograft tumors derived from these cells also displayed enhanced expression of cyclin D1 and c-Myc along with antiapoptotic genes encoding Bcl-x(L), and XIAP, and failed to develop the extensive necrotic zones and edema observed in control tumors. Surprisingly, 4E-BP1 knock-down also leads to a dramatic increase in aberrant mitoses in vivo and enhanced expression of Mad2 and securin. Thus, reduced e...Continue Reading

Citations

Oct 1, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Mei Yee KohGarth Powis
Aug 20, 2011·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Silke ReinartzUwe Wagner
Apr 13, 2012·Medicinal Research Reviews·Yan JiaCarston R Wagner
Dec 20, 2011·Biochimica Et Biophysica Acta·Macarena Hernández-JiménezVíctor M González
Feb 26, 2016·British Journal of Haematology·Ma Carmen Herrero-SánchezBelén Blanco
Mar 3, 2011·Nature Reviews. Clinical Oncology·Sarah P Blagden, Anne E Willis
Oct 22, 2016·Journal of Hematology & Oncology·Mª Carmen Herrero-SánchezBelén Blanco
Jun 1, 2013·Cancer Research·Latika KohliKevin A Roth
Apr 1, 2021·Cellular & Molecular Immunology·Shree Padma Metur, Daniel J Klionsky

❮ Previous
Next ❯

Related Concepts

Related Feeds

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.