Involvement of the proteasome in the programmed cell death of NGF-deprived sympathetic neurons.

Abstract

Sympathetic neurons undergo programmed cell death (PCD) upon deprivation of nerve growth factor (NGF). PCD of neurons is blocked by inhibitors of the interleukin‐1beta converting enzyme (ICE)/Ced‐3‐like cysteine protease, indicating involvement of this class of proteases in the cell death programme. Here we demonstrate that the proteolytic activities of the proteasome are also essential in PCD of neurons. Nanomolar concentrations of several proteasome inhibitors, including the highly selective inhibitor lactacystin, not only prolonged survival of NGF‐deprived neurons but also prevented processing of poly(ADP‐ribose) polymerase which is known to be cleaved by an ICE/Ced‐3 family member during PCD. These results demonstrate that the proteasome is a key regulator of neuronal PCD and that, within this process, it is involved upstream of proteases of the ICE/Ced‐3 family. This order of events was confirmed in macrophages where lactacystin inhibited the proteolytic activation of precursor ICE and the subsequent generation of active interleukin‐1beta.

Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional Bcl-2 and p53

“…Inhibition of proteasome activity does not, however, invariably result in cell death induction and may, in some circumstances result in survival enhancement (Grimm et al, 1996;Sadoul et al, 1996). These divergent results may be reconciled, should the inhibition of proteasomal activity have di erent e ects on quiescent cells or di erentiated cells versus actively cycling tumor cells as reported (Drexler, 1997;Lopes et al, 1997;Tanimoto et al, 1997;Wu et al, 1996).…”

Enhancement of TNF‐α‐mediated cell death in vascular smooth muscle cells through cytochrome c‐independent pathway by the proteasome inhibitor

“…For example, proteasome inhibitors protected cells from apoptosis induced by some but not all stimuli. Programmed cell death of sympathetic neurons upon deprivation of nerve growth factor was delayed by proteasome inhibitors [22]. In thymocytes, proteasome inhibition blocked apoptosis induced by ionizing radiation, glucocorticoids, or phorbol esters [23].…”

Endoplasmic reticulum stress-induced cell death mediated by the proteasome

“…22 Pro-apoptotic functions of the proteasome have been described in several instances including the constitutive death of neutrophils as well as NGF withdrawal, DNA damage, glucocorticoid treatment and reduced extracellular potassium. [23][24][25][26][27] Additionally, the proteasome has been implicated in the early stages of wallerian degeneration after axotomy. 28 In response to DNA damage, the large Bcl-2 homology domain-only protein Mule/ARF-BP1 was shown to ubiquitylate Mcl-1 -an anti-apoptotic Bcl-2 family member -thereby causing its degradation via the proteasome.…”