On the involvement of calpains in the degradation of the tumor suppressor protein p53

Gonen, Hedva; Shkedy, Dganit; Barnoy, Sivia; Kosower, Nechama S.; Ciechanover, Aaron

doi:10.1016/s0014-5793(97)00225-1

Cited by 83 publications

(55 citation statements)

References 25 publications

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“…Thus the ATP-dependent degradation of N-myc, which is thought to be mediated by the proteasome, can be inhibited by immunologic depletion of the E1 ubiquitin-activating enzyme (Ciechanover et al, 1991(Ciechanover et al, , 1994. At the same time, as previously shown for ornithine decarboxylase Rosenberg-Hasson et al, 1989), c-Jun (Jariel-Encontre et al, 1995) and p53 (Gonen et al, 1997), in vitro degradation of N-myc can also proceed via a calpaindependent ubiquitin-independent pathway (Gonen et al, 1997).…”

Section: Discussionsupporting

confidence: 56%

“…The involvement of an ATP-dependent degradation pathway in vitro in the turnover of N-myc and other nuclear regulatory proteins (c-Myc, c-Fos, E1A and p53) has been demonstrated, however high molecular weight ubiquitin conjugates of N-myc were not observed (Ciechanover et al, 1991). In addition, a recent in vitro study has also implicated calpain in N-myc degradation (Gonen et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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In vivo degradation of N-myc in neuroblastoma cells is mediated by the 26S proteasome

et al. 1998

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

In vivo degradation of N-myc in neuroblastoma cells is mediated by the 26S proteasome

et al. 1998

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“…Induction of wild type p53 in MCF7 is a positive control for PS-341 activity resistant to ALLN (Figures 2a and 3c). Accumulation of wild type p53, previously shown to be sensitive to calpain as well as proteasome inhibition (Gonen et al, 1997;Kubbutat and Vousden, 1997;Pariat et al, 1997;Zhang et al, 1997), was demonstrated in MCF10 cells at the concentrations/incubation times used of the calpain inhibitors calpastatin peptide and PD150606 (Figure 4b). …”

Section: Brca1 Protein Accumulated After Alln Has An Increased Half-lifementioning

confidence: 76%

Regulation of BRCA1 by protein degradation

et al. 1999

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BRCA1, a tumor suppressor protein implicated in hereditary forms of breast and ovarian cancer, is transcriptionally regulated in a proliferation-dependent manner. In this study, we demonstrate a substantial role for proteolysis in regulating the BRCA1 steady-state protein level in several cell lines. N-acetyl-leu-leunorleucinal (ALLN), an inhibitor of the proteasome, calpain, and cathepsins, caused BRCA1 protein to accumulate in the nucleus of several human breast, prostate, and melanoma cell lines which express low or undetectable basal levels of BRCA1 protein, but not in cells with high basal expression of BRCA1. Protease inhibition did not increase BRCA1 synthesis, nor change its mRNA level, but it dramatically prolonged the protein's half-life. In contrast to ALLN, lactacystin and PS341, two speci®c proteasome inhibitors, as well as calpastatin peptide and PD150606, two selective calpain inhibitors, had no e ect on BRCA1 stability, whereas ALLM, an e ective calpain and cathepsin inhibitor but weak proteasome inhibitor, did stimulate accumulation of BRCA1. Moreover, three inhibitors of acidic cysteine proteases, chloroquine, ammonium chloride and ba®lo-mycin, were as e ective as ALLN. These results demonstrate that degradation by a cathepsin-like protease in ®ne balance with BRCA1 transcription is responsible for maintaining the low steady-state level of BRCA1 protein seen in many cancer cells.

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“…WT p53 is degraded through proteasomes (Ciechanover, 1994) and by calpain Zhang et al, 1997;Gonen et al, 1997) and inhibition of proteasomes leads to accumulation of wt p53 (Maki et al, 1996;Blagosklonny et al, 1996b;Dietrich et al, 1996). Similarly, the levels of wt p53, can be increased by DNA-damaging agents (Maltzman and Czyzyk, 1984 ;Kastan et al, 1991Kastan et al, , 1992Fritsche et al, 1993), and some other stimuli.…”

mentioning

confidence: 99%

Loss of function and p53 protein stabilization

Blagosklonny

1997

Oncogene

127

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Wild-type (wt) p53 protein is rapidly degraded, has a short half-life and low intracellular levels. Stabilization of wt p53 protein following an appropriate stimulus (for example DNA damage) is a physiological regulation to increase function. In contrast, stabilization of p53 protein in the absence of a stimulus is always a hallmark of loss of function secondary to a mutation, or interaction with viral or cellular oncoproteins. It is generally accepted that stability of p53 protein depends on its intrinsic biochemical properties such as conformation or protein/protein interactions. However, I will discuss evidence that the stability of p53 is not a consequence of its intrinsic properties, but instead is determined by feedback control of its function. In the absence of an appropriate stimulus, a cell needs to keep p53 levels low, since increased levels can lead to apoptosis. To precisely regulate p53 levels, a cell must sense its level; and sensing its transactivating function, is the simplest way to sense p53. Following an appropriate stimulus (for example, DNA damage), the cell senses a state of`relative' p53 de®ciency and adapts by reducing p53 degradation. When the state of p53 de®ciency is a consequence of a mutation or interaction with viral oncoproteins, the cell does not sense p53, and again attempts to adapt by reducing p53 degradation. However, in the latter case, the increase in levels does not restore function, and the adaptation continues until degradation of p53 protein is maximally inhibited. In this case, no further inhibition of degradation is possible after DNA-damage or pharmacological inhibition of proteasomes. Thus lack of wt p53 function always results in increased p53 levels and nonregulation.

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On the involvement of calpains in the degradation of the tumor suppressor protein p53

Cited by 83 publications

References 25 publications

In vivo degradation of N-myc in neuroblastoma cells is mediated by the 26S proteasome

In vivo degradation of N-myc in neuroblastoma cells is mediated by the 26S proteasome

Regulation of BRCA1 by protein degradation

Loss of function and p53 protein stabilization

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