Synchronised phosphorylation of BNIP3, Bcl-2 and Bcl-xL in response to microtubule-active drugs is JNK-independent and requires a mitotic kinase

Biochemical Pharmacology
Howard R MellorAdrian L Harris

Abstract

BNIP3 is a hypoxia-inducible BH3-only member of the Bcl-2 family of proteins that regulate apoptosis and autophagy. However the role of BNIP3 in the hypoxia response has proved difficult to define and remains controversial. In this study we show that in cancer cells, knockdown or forced expression of BNIP3 fails to modulate cell survival under hypoxic or normoxic conditions. However, we demonstrate that BNIP3 is regulated post-translationally, existing as multiple monomeric and dimeric phosphorylated forms. Upon treatment with microtubule inhibitors, but not other classes of chemotherapeutics, BNIP3 becomes hyperphosphorylated. We demonstrate that the phosphorylation of BNIP3 occurs in synchrony with phosphorylation of its binding partners Bcl-2 and Bcl-xL. Microtubule inhibitor-induced phosphorylation of these proteins occurs independently of the AKT/mTor and JNK kinase pathways and requires Mps1 mitotic checkpoint kinase activity. Inhibition of mitotic arrest in the presence of paclitaxel blocks the phosphorylation of BNIP3, Bcl-2 and Bcl-xL, demonstrating that these proteins are phosphorylated by a mitochondrially active mitotic kinase. We show that phosphorylation increases the stability of BNIP3 and that BNIP3 predominantl...Continue Reading

References

Feb 12, 1998·The Journal of Experimental Medicine·G ChenA H Greenberg
Jul 21, 1998·The Journal of Biological Chemistry·Y H LingR Perez-Soler
Nov 7, 1998·The Journal of Biological Chemistry·C D ScatenaJ A Pietenpol
Mar 31, 1999·Proceedings of the National Academy of Sciences of the United States of America·R K SrivastavaD L Longo
Sep 2, 1999·Biochemical and Biophysical Research Communications·P ChadebechA Valette
Jun 6, 2000·The Journal of Biological Chemistry·Y TanM J Comb
Aug 2, 2000·Proceedings of the National Academy of Sciences of the United States of America·R K Bruick
Nov 21, 2000·The Journal of Biological Chemistry·S VermaG Chinnadurai
Dec 12, 2000·The Journal of Biological Chemistry·L B GardnerC V Dang
Sep 11, 2001·Cell Death and Differentiation·K GuoY Ivashchenko
Nov 22, 2001·Proceedings of the National Academy of Sciences of the United States of America·B L BennettD W Anderson
Mar 21, 2002·Nature Reviews. Cancer·Adrian L Harris
Sep 13, 2002·Proceedings of the National Academy of Sciences of the United States of America·Lori A KubasiakKeith A Webster
Dec 17, 2002·Molecular and Cellular Biology·Nobuhito GodaRandall S Johnson
Sep 18, 2003·Nature Reviews. Cancer·Gregg L Semenza
Dec 9, 2003·Proceedings of the National Academy of Sciences of the United States of America·Xingming DengW Stratford May
Feb 10, 2004·The Journal of Biological Chemistry·James F Curtin, Thomas G Cotter
Apr 2, 2004·Nature Reviews. Cancer·Mary Ann Jordan, Leslie Wilson
Oct 16, 2004·Proceedings of the National Academy of Sciences of the United States of America·Hisashi HaradaStanley J Korsmeyer
Aug 23, 2005·EMBO Reports·Marc SchmidtRené H Medema
Oct 26, 2005·Current Opinion in Cell Biology·Simon N Willis, Jerry M Adams
Nov 2, 2005·The Journal of Cell Biology·Tomoya YamaguchiMasaki Inagaki
Apr 29, 2006·Cell Death and Differentiation·V LabiA Villunger
Apr 29, 2006·Cell Death and Differentiation·A Hamacher-BradyA B Gustafsson
Jun 20, 2007·Molecular and Cellular Biology·Kristin TracyKay F Macleod
Dec 22, 2007·Nature Reviews. Molecular Cell Biology·Richard J Youle, Andreas Strasser
Feb 19, 2008·The Journal of Biological Chemistry·Huafeng ZhangGregg L Semenza
Mar 4, 2008·Trends in Cell Biology·Jerry E Chipuk, Douglas R Green
May 24, 2008·Autophagy·Beth LevineGuido Kroemer
Jun 14, 2008·Cell Death and Differentiation·I PapandreouN C Denko
Jan 27, 2009·Proceedings of the National Academy of Sciences of the United States of America·KangAe LeeGregg L Semenza

❮ Previous
Next ❯

Citations

Apr 7, 2010·Biochemical and Biophysical Research Communications·Ivana NikolicMarina Mitrovic
Jan 10, 2014·The Journal of Investigative Dermatology·Mariko MoriyamaTakao Hayakawa
Jan 11, 2013·Journal of Cellular and Molecular Medicine·Mayur V JainMarek Łos
May 4, 2011·Cell Transplantation·Peter D CampbellHelen E Thomas
Aug 15, 2014·Molecular Cancer Therapeutics·Carolina CastillaCarmen Sáez
Jul 1, 2021·World Journal of Clinical Oncology·Alejandro EspañolMaría Elena Sales

❮ 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

Autophagy & Metabolism

Autophagy preserves the health of cells and tissues by replacing outdated and damaged cellular components with fresh ones. In starvation, it provides an internal source of nutrients for energy generation and, thus, survival. A powerful promoter of metabolic homeostasis at both the cellular and whole-animal level, autophagy prevents degenerative diseases. It does have a downside, however--cancer cells exploit it to survive in nutrient-poor tumors.

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.

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.

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms