J Korean Med Sci.  2001 Apr;16(2):135-139. 10.3346/jkms.2001.16.2.135.

The Levels of MDM2 Protein Are Decreased by a Proteasome-Mediated Proteolysis Prior to Caspase-3-Dependent pRb and PARP Cleavages

• Cho JW
• Park JC
• Lee JC
• Kwon TK
• Park JW
• Baek WK
• Suh SI
• Suh MH

• KMID: 648246
• DOI: http://doi.org/10.3346/jkms.2001.16.2.135

Abstract

MDM2 is a substrate of caspase-3 in p53-mediated apoptosis. In addition, MDM2 mediates its own ubiquitination in a RING finger-dependent manner. Thus, we investigated whether MDM2 is degraded through a ubiquitin-dependent proteasome pathway in the absence of p53. When HL-60 cells, p53 null, were treated with etoposide, MDM2 was markedly decreased prior to caspase-3-dependent retinoblastoma tumor suppressor protein (pRb) and poly (ADP- ribose) polymerase (PARP) cleavages. Moreover, down-regulation of MDM2 level was not coupled with its mRNA down-regulation. However, the level of MDM2 was partially restored by proteasome inhibitors such as LLnL and lactacystin, even in the presence of etoposide. Our results suggest that, in the p53 null status, MDM2 protein level is decreased by proteasome-mediated proteolysis prior to caspase-3-dependent PARP and pRb cleavages.

Keyword

HL-60 Cells; Ubiquitin; Apoptosis

MeSH Terms

Antineoplastic Agents, Phytogenic/pharmacology
Apoptosis/drug effects/physiology
Caspases/*metabolism
Cysteine Endopeptidases/*metabolism
Down-Regulation (Physiology)/physiology
Etoposide/pharmacology
HL-60 Cells
Human
Multienzyme Complexes/*metabolism
NAD+ ADP-Ribosyltransferase/*metabolism
Proto-Oncogene Proteins/*metabolism
Retinoblastoma Protein/*metabolism