A functional role for death proteases in s-Myc- and c-Myc-mediated apoptosis

Shigehide Kagaya, Chifumi Kitanaka, Kohji Noguchi, Toshihiro Mochizuki, Akinori Sugiyama, Akio Asai, Noriko Yasuhara, Yutaka Eguchi, Yoshihide Tsujimoto, Yoshiyuki Kuchino

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

Upon activation, cell surface death receptors, Fas/APO-1/CD95 and tumor necrosis factor receptor-1 (TNFR-1), are attached to cytosolic adaptor proteins, which in turn recruit caspase-8 (MACH/FLICE/Mch5) to activate the interleukin-1 β-converting enzyme (ICE)/CED-3 family protease (caspase) cascade. However, it remains unknown whether these apoptotic proteases are generally involved in apoptosis triggered by other stimuli such as Myc and p53. In this study, we provide lines of evidence that a death protease cascade consisting of caspases and serine proteases plays an essential role in Myc-mediated apoptosis. When Rat-1 fibroblasts stably expressing either s- Myc or c-Myc were induced to undergo apoptosis by serum deprivation, a caspase-3 (CPP32)-like protease activity that cleaves a specific peptide substrate, Ac-DEVD-MCA, appeared in the cell lysates. Induction of s-Myc- and c-Myc-mediated apoptotic cell death was effectively prevented by caspase inhibitors such as Z-Asp-CH2-DCB and Ac-DEVD-CHO. Furthermore, exposing the cells to a serine protease inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), also significantly inhibited s-Myc- and c-Myc-mediated apoptosis and the appearance of the caspase-3-like protease activity in vivo. However, AEBSF did not directly inhibit caspase-3-like protease activity in the apoptotic cell lysates in vitro. Together, these results indicate that caspase-3-like proteases play a critical role in both s-Myc- and c-Myc- mediated apoptosis and that caspase-3-like proteases function downstream of the AEBSF-sensitive step in the signaling pathway of Myc-mediated apoptosis.

Original languageEnglish
Pages (from-to)6736-6745
Number of pages10
JournalMolecular and cellular biology
Volume17
Issue number11
DOIs
Publication statusPublished - 1997 Nov

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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