Heat shock protein 70 inhibits shrinkage-induced programmed cell death via mechanisms independent of effects on cell volume-regulatory membrane transport proteins.

J Nylandsted; M Jäättelä; E K Hoffmann; Stine Helene Falsig Pedersen

doi:10.1007/s00424-004-1332-z

Heat shock protein 70 inhibits shrinkage-induced programmed cell death via mechanisms independent of effects on cell volume-regulatory membrane transport proteins.

J Nylandsted, M Jäättelä, E K Hoffmann, Stine Helene Falsig Pedersen

Cell Biology and Physiology

29 Citations (Scopus)

Abstract

Cell shrinkage is a ubiquitous feature of programmed cell death (PCD), but whether it is an obligatory signalling event in PCD is unclear. Heat shock protein 70 (Hsp70) potently counteracts PCD in many cells, by mechanisms that are incompletely understood. In the present investigation, we found that severe hypertonic stress greatly diminished the viability of murine fibrosarcoma cells (WEHI-902) and immortalized murine embryonic fibroblasts (iMEFs). This effect was attenuated markedly by Hsp70 over-expression. To determine whether the protective effect of Hsp70 was mediated via an effect on volume regulatory ion transport, we compared regulatory volume decrease (RVD) and increase (RVI) in control WEHI-902 cells and after increasing Hsp70 levels by heat shock or over-expression (WEHI-912). Hsp70 levels affected neither RVD, RVI nor the relative contributions of the Na(+)/H(+)-exchanger (NHE1) and Na(+),K(+),2Cl(-)-cotransporter (NKCC1) to RVI. Hypertonic stress induced caspase-3 activity in WEHI cells and iMEFs, an effect potentiated by Hsp70 in WEHI cells but inhibited by Hsp70 in iMEFs. Osmotic shrinkage-induced PCD was associated with Hsp70-inhibitable cysteine cathepsin release in iMEFs and attenuated by caspase and cathepsin inhibitors in WEHI cells. Treatment with TNF-alpha or the NHE1 inhibitor 5'-(N-ethyl-N-isopropyl)amiloride (EIPA) reduced the viability of WEHI cells further under isotonic and mildly, but not severely, hypertonic conditions. Thus, it is concluded that shrinkage-induced PCD involves both caspase- and cathepsin-dependent death mechanisms and is potently counteracted by Hsp70.

Original language	English
Journal	Pflügers Archiv: European Journal of Physiology
Volume	449
Issue number	2
Pages (from-to)	175-85
Number of pages	10
ISSN	0031-6768
DOIs	https://doi.org/10.1007/s00424-004-1332-z
Publication status	Published - 2004

Access to Document

10.1007/s00424-004-1332-z

Cite this

Heat shock protein 70 inhibits shrinkage-induced programmed cell death via mechanisms independent of effects on cell volume-regulatory membrane transport proteins. / Nylandsted, J; Jäättelä, M; Hoffmann, E K et al.

In: Pflügers Archiv: European Journal of Physiology, Vol. 449, No. 2, 2004, p. 175-85.

Research output: Contribution to journal › Journal article › Research › peer-review

@article{38779100a0f311dd86a6000ea68e967b,

title = "Heat shock protein 70 inhibits shrinkage-induced programmed cell death via mechanisms independent of effects on cell volume-regulatory membrane transport proteins.",

abstract = "Cell shrinkage is a ubiquitous feature of programmed cell death (PCD), but whether it is an obligatory signalling event in PCD is unclear. Heat shock protein 70 (Hsp70) potently counteracts PCD in many cells, by mechanisms that are incompletely understood. In the present investigation, we found that severe hypertonic stress greatly diminished the viability of murine fibrosarcoma cells (WEHI-902) and immortalized murine embryonic fibroblasts (iMEFs). This effect was attenuated markedly by Hsp70 over-expression. To determine whether the protective effect of Hsp70 was mediated via an effect on volume regulatory ion transport, we compared regulatory volume decrease (RVD) and increase (RVI) in control WEHI-902 cells and after increasing Hsp70 levels by heat shock or over-expression (WEHI-912). Hsp70 levels affected neither RVD, RVI nor the relative contributions of the Na(+)/H(+)-exchanger (NHE1) and Na(+),K(+),2Cl(-)-cotransporter (NKCC1) to RVI. Hypertonic stress induced caspase-3 activity in WEHI cells and iMEFs, an effect potentiated by Hsp70 in WEHI cells but inhibited by Hsp70 in iMEFs. Osmotic shrinkage-induced PCD was associated with Hsp70-inhibitable cysteine cathepsin release in iMEFs and attenuated by caspase and cathepsin inhibitors in WEHI cells. Treatment with TNF-alpha or the NHE1 inhibitor 5'-(N-ethyl-N-isopropyl)amiloride (EIPA) reduced the viability of WEHI cells further under isotonic and mildly, but not severely, hypertonic conditions. Thus, it is concluded that shrinkage-induced PCD involves both caspase- and cathepsin-dependent death mechanisms and is potently counteracted by Hsp70.",

author = "J Nylandsted and M J{\"a}{\"a}ttel{\"a} and Hoffmann, {E K} and Pedersen, {Stine Helene Falsig}",

note = "Keywords: Animals; Apoptosis; Caspases; Cathepsins; Cation Transport Proteins; Cell Line, Tumor; Cell Size; Fibrosarcoma; HSP70 Heat-Shock Proteins; Homeostasis; Hypertonic Solutions; Membrane Proteins; Mice; Osmotic Pressure; Signal Transduction; Sodium-Hydrogen Antiporter; Tumor Necrosis Factor-alpha",

year = "2004",

doi = "10.1007/s00424-004-1332-z",

language = "English",

volume = "449",

pages = "175--85",

journal = "Pfl{\"u}gers Archiv - European Journal of Physiology",

issn = "0031-6768",

publisher = "Springer",

number = "2",

}

TY - JOUR

T1 - Heat shock protein 70 inhibits shrinkage-induced programmed cell death via mechanisms independent of effects on cell volume-regulatory membrane transport proteins.

AU - Nylandsted, J

AU - Jäättelä, M

AU - Hoffmann, E K

AU - Pedersen, Stine Helene Falsig

N1 - Keywords: Animals; Apoptosis; Caspases; Cathepsins; Cation Transport Proteins; Cell Line, Tumor; Cell Size; Fibrosarcoma; HSP70 Heat-Shock Proteins; Homeostasis; Hypertonic Solutions; Membrane Proteins; Mice; Osmotic Pressure; Signal Transduction; Sodium-Hydrogen Antiporter; Tumor Necrosis Factor-alpha

PY - 2004

Y1 - 2004

N2 - Cell shrinkage is a ubiquitous feature of programmed cell death (PCD), but whether it is an obligatory signalling event in PCD is unclear. Heat shock protein 70 (Hsp70) potently counteracts PCD in many cells, by mechanisms that are incompletely understood. In the present investigation, we found that severe hypertonic stress greatly diminished the viability of murine fibrosarcoma cells (WEHI-902) and immortalized murine embryonic fibroblasts (iMEFs). This effect was attenuated markedly by Hsp70 over-expression. To determine whether the protective effect of Hsp70 was mediated via an effect on volume regulatory ion transport, we compared regulatory volume decrease (RVD) and increase (RVI) in control WEHI-902 cells and after increasing Hsp70 levels by heat shock or over-expression (WEHI-912). Hsp70 levels affected neither RVD, RVI nor the relative contributions of the Na(+)/H(+)-exchanger (NHE1) and Na(+),K(+),2Cl(-)-cotransporter (NKCC1) to RVI. Hypertonic stress induced caspase-3 activity in WEHI cells and iMEFs, an effect potentiated by Hsp70 in WEHI cells but inhibited by Hsp70 in iMEFs. Osmotic shrinkage-induced PCD was associated with Hsp70-inhibitable cysteine cathepsin release in iMEFs and attenuated by caspase and cathepsin inhibitors in WEHI cells. Treatment with TNF-alpha or the NHE1 inhibitor 5'-(N-ethyl-N-isopropyl)amiloride (EIPA) reduced the viability of WEHI cells further under isotonic and mildly, but not severely, hypertonic conditions. Thus, it is concluded that shrinkage-induced PCD involves both caspase- and cathepsin-dependent death mechanisms and is potently counteracted by Hsp70.

AB - Cell shrinkage is a ubiquitous feature of programmed cell death (PCD), but whether it is an obligatory signalling event in PCD is unclear. Heat shock protein 70 (Hsp70) potently counteracts PCD in many cells, by mechanisms that are incompletely understood. In the present investigation, we found that severe hypertonic stress greatly diminished the viability of murine fibrosarcoma cells (WEHI-902) and immortalized murine embryonic fibroblasts (iMEFs). This effect was attenuated markedly by Hsp70 over-expression. To determine whether the protective effect of Hsp70 was mediated via an effect on volume regulatory ion transport, we compared regulatory volume decrease (RVD) and increase (RVI) in control WEHI-902 cells and after increasing Hsp70 levels by heat shock or over-expression (WEHI-912). Hsp70 levels affected neither RVD, RVI nor the relative contributions of the Na(+)/H(+)-exchanger (NHE1) and Na(+),K(+),2Cl(-)-cotransporter (NKCC1) to RVI. Hypertonic stress induced caspase-3 activity in WEHI cells and iMEFs, an effect potentiated by Hsp70 in WEHI cells but inhibited by Hsp70 in iMEFs. Osmotic shrinkage-induced PCD was associated with Hsp70-inhibitable cysteine cathepsin release in iMEFs and attenuated by caspase and cathepsin inhibitors in WEHI cells. Treatment with TNF-alpha or the NHE1 inhibitor 5'-(N-ethyl-N-isopropyl)amiloride (EIPA) reduced the viability of WEHI cells further under isotonic and mildly, but not severely, hypertonic conditions. Thus, it is concluded that shrinkage-induced PCD involves both caspase- and cathepsin-dependent death mechanisms and is potently counteracted by Hsp70.

U2 - 10.1007/s00424-004-1332-z

DO - 10.1007/s00424-004-1332-z

M3 - Journal article

C2 - 15340851

SN - 0031-6768

VL - 449

SP - 175

EP - 185

JO - Pflügers Archiv - European Journal of Physiology

JF - Pflügers Archiv - European Journal of Physiology

IS - 2

ER -

Heat shock protein 70 inhibits shrinkage-induced programmed cell death via mechanisms independent of effects on cell volume-regulatory membrane transport proteins.

Abstract

Access to Document

Fingerprint

Cite this