Cleavage of Bax Enhances Its Cell Death Function

Cleavage of Bax Enhances Its Cell Death Function Members of the Bcl-2 family of proteins are key regulators of apoptosis. Some of these proteins undergo posttranslational modification, such as phosphorylation or proteolysis, that serves to alter their function. Caspases are known to cleave Bid, a proapoptotic family member, as well as Bcl-2 and Bcl-X L , two prosurvival family members, which activate their cytotoxic activity resulting in the release of cytochrome c from mitochondria. Previously we showed that Bax was cleaved by calpain rather than by caspases from full-length 21 kDa to generate a cleavage fragment of 18 kDa. Since cleavage of Bid serves to activate its cytotoxic activity, we wanted to determine if the p18 form of Bax exhibited increased cytotoxicity compared to p21 Bax. Using a transient transfection system in human embryonic kidney 293T cells we show that the p18 form of Bax displays a more potent ability to induce cell death. The pancaspase inhibitor Z-VAD-fmk completely blocked apoptosis induced by p21 Bax but only partially inhibited apoptosis induced by p18 Bax. Cyclosporin A, an inhibitor of the mitochondrial permeability transition (PT) pore, had no effect on Bax-mediated apoptosis of 293T cells suggesting that apoptosis was independent of the PT. Thus cleavage of p21 Bax during apoptosis to the p18 form may serve to increase the intrinsic cytotoxic properties of this proapoptotic molecule and enhance its cell death function at the mitochondria. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Experimental Cell Research Elsevier

Cleavage of Bax Enhances Its Cell Death Function

Loading next page...
 
/lp/elsevier/cleavage-of-bax-enhances-its-cell-death-function-sdkpdRHHuu
Publisher
Elsevier
Copyright
Copyright © 2000 Academic Press
ISSN
0014-4827
DOI
10.1006/excr.2000.4859
Publisher site
See Article on Publisher Site

Abstract

Members of the Bcl-2 family of proteins are key regulators of apoptosis. Some of these proteins undergo posttranslational modification, such as phosphorylation or proteolysis, that serves to alter their function. Caspases are known to cleave Bid, a proapoptotic family member, as well as Bcl-2 and Bcl-X L , two prosurvival family members, which activate their cytotoxic activity resulting in the release of cytochrome c from mitochondria. Previously we showed that Bax was cleaved by calpain rather than by caspases from full-length 21 kDa to generate a cleavage fragment of 18 kDa. Since cleavage of Bid serves to activate its cytotoxic activity, we wanted to determine if the p18 form of Bax exhibited increased cytotoxicity compared to p21 Bax. Using a transient transfection system in human embryonic kidney 293T cells we show that the p18 form of Bax displays a more potent ability to induce cell death. The pancaspase inhibitor Z-VAD-fmk completely blocked apoptosis induced by p21 Bax but only partially inhibited apoptosis induced by p18 Bax. Cyclosporin A, an inhibitor of the mitochondrial permeability transition (PT) pore, had no effect on Bax-mediated apoptosis of 293T cells suggesting that apoptosis was independent of the PT. Thus cleavage of p21 Bax during apoptosis to the p18 form may serve to increase the intrinsic cytotoxic properties of this proapoptotic molecule and enhance its cell death function at the mitochondria.

Journal

Experimental Cell ResearchElsevier

Published: May 1, 2000

References

  • Alphaviruses induce apoptosis in Bcl-2-overexpressing cells: Evidence for a caspase-mediated, proteolytic inactivation of Bcl-2
    Grandgirad, D.; Studer, E.; Monney, L.; Belser, T.; Fellay, I.; Borner, C.; Michel, M.R.
  • Regulated targeting of BAX to mitochondria
    Goping, I.S.; Gross, A.; Lavoie, J.N.; Nguyen, M.; Jemmerson, R.; Roth, K.; Korsmeyer, S.J.; Shore, G.C.
  • The permeability transition pore complex: A target for apoptosis regulation by caspases and Bcl-2-related proteins
    Marzo, I.; Brenner, C.; Zamzami, N.; Susin, S.A.; Beutner, G.; Brdiczka, D.; Remy, R.; Xie, Z-H.; Reed, J.C.; Kroemer, G.
  • Induction of the mitochondrial permeability transition by protease activity in rats: A mechanism of hepatocyte necrosis
    Aguilar, H.I.; Ravi, B.; Arora, A.S.; Bronk, S.F.; Gores, G.J.
  • Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization
    Bossy-Wetzel, E.; Newmeyer, D.D.; Green, D.R.
  • Collapse of the inner mitochondrial transmembrane potential is not required for apoptosis of HL60 cells
    Finucane, D.M.; Waterhouse, N.J.; Amarante-Mendes, G.P.; Cotter, T.G.; Green, D.R.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create folders to
organize your research

Export folders, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off