TNF down-regulation of receptor tyrosine kinase-dependent mitogenic signal pathways as an important step in cytostasis induction and commitment to apoptosis of Kym-1 rhabdomyosarcoma cells

Peter Storz, H. Doppler, J. Horn-Muller, G. Muller, K. Pfizenmaier

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Growth of Kym-1 rhabdomyosarcoma cells depends on endogenous receptor tyrosine kinase signals activated by insulin and insulin-like growth factors (IGF), as revealed from enhancement of proliferation by insulin and IGF-1 and cytostatic action of inhibitors of IR/IGFR kinases. Depending on the presence or absence of the caspase inhibitor z-VAD-fmk, TNF induced full growth arrest or apoptosis, respectively, indicating dominance of TNF over mitogenic signal pathways in Kym-1 cells. In accordance with a caspase-independent cytostatic action, TNF downregulated IR kinase activity and caused a profound inhibition of downstream mitogenic signals including the MAPK cascade and STAT5, key pathways of proliferation and cell survival. Removal of z-VAD-fmk after 24 h induced rapid cell death in the absence of TNF. The inhibition of survival signals concomitant with persisting proapoptotic signals may tip the balance towards an irreversible commitment of the cell to apoptosis that becomes apparent upon relief of suppression of effector caspases.

Original languageEnglish (US)
Pages (from-to)955-965
Number of pages11
JournalCell Death and Differentiation
Volume7
Issue number10
StatePublished - 2000
Externally publishedYes

Fingerprint

Receptor Protein-Tyrosine Kinases
Signal Transduction
Down-Regulation
Cytostatic Agents
Somatomedins
Apoptosis
Phosphotransferases
Effector Caspases
Insulin
Caspase Inhibitors
Growth
Caspases
Cell Survival
Cell Death
Rhabdomyosarcoma 1

Keywords

  • Apoptosis
  • Growth arrest
  • MAPK pathway
  • STAT5
  • TNF signal crosstalk

ASJC Scopus subject areas

  • Cell Biology

Cite this

TNF down-regulation of receptor tyrosine kinase-dependent mitogenic signal pathways as an important step in cytostasis induction and commitment to apoptosis of Kym-1 rhabdomyosarcoma cells. / Storz, Peter; Doppler, H.; Horn-Muller, J.; Muller, G.; Pfizenmaier, K.

In: Cell Death and Differentiation, Vol. 7, No. 10, 2000, p. 955-965.

Research output: Contribution to journalArticle

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AU - Doppler, H.

AU - Horn-Muller, J.

AU - Muller, G.

AU - Pfizenmaier, K.

PY - 2000

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