Endoproteolytic Activity of the Proteasome

Liu, Chang Wei; Corboy, Michael J.; DeMartino, George N.; Thomas, Philip

doi:10.1126/science.1079293

Cited by 400 publications

(365 citation statements)

References 30 publications

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“…In many cases, if a protein can be delivered to the proteasome in a denatured or partially unfolded state, ubiquitination should not be required for its degradation. In fact, p21 and a-synuclein that are considered 'naturally unstructured' proteins can be degraded in vitro by the proteasome, in the absence of ubiquitination (Liu et al, 2003). It has been reported that ARF can be subjected to N-terminal ubiquitination, a process independent from p53 and Mdm2 (Kuo et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro translated p14ARF was incubated with 20S proteasome at 371C for the indicated time intervals (Figure 6d). As controls, we used in vitro translated p21, that has been shown to be naturally unstructured and degraded in vitro by the 20S proteasome (Liu et al, 2003) and TBP-1. As shown, ARF is degraded by the 20S proteasome as efficiently as p21 and accumulates after treatment with proteasome inhibitor, whereas TBP-1 levels are unchanged.…”

Section: Tbp-1 Regulates P14arf Oncosuppressor a Pollice Et Almentioning

confidence: 99%

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TBP-1 protects the human oncosuppressor p14ARF from proteasomal degradation

et al. 2007

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The p14ARF tumor suppressor is a key regulator of cellular proliferation, frequently inactivated in human cancer. The mechanisms that regulate alternative reading frame (ARF) turnover have been obscure for long time, being ARF a relatively stable protein. Recently, it has been described that its degradation depends, at least in part, on the proteasome and that it can be subjected to N-terminal ubiquitination. We have previously reported that ARF protein levels are regulated by TBP-1 (Tat-Binding Protein 1), a multifunctional protein, component of the regulatory subunit of the proteasome, involved in different cellular processes. Here we demonstrate that the stabilization effect exerted by TBP-1 requires an intact N-terminal 39 amino acids in ARF and occurs independently from N-terminal ubiquitination of the protein. Furthermore, we observed that ARF can be degraded in vitro by the 20S proteasome, in the absence of ubiquitination and this effect can be counteracted by TBP-1. These observations seem relevant in the comprehension of the regulation of ARF metabolism as, among the plethora of cellular ARF's interactors already identified, only NPM/B23 and TBP-1 appear to be involved in the control of ARF intracellular levels.

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Section: Discussionmentioning

confidence: 99%

Section: Tbp-1 Regulates P14arf Oncosuppressor a Pollice Et Almentioning

confidence: 99%

TBP-1 protects the human oncosuppressor p14ARF from proteasomal degradation

et al. 2007

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“…Investigations of substrate binding, release and degradation of side-on and bottom immobilized proteasomes revealed that one entry to the proteolytic chamber is sufficient for substrate access and release of the products (125). A positive cooperativity of substrate binding has been shown: The proteasome can degrade two substrates at the same time, as well as it can cleave proteins without accessible ''ends'' while showing endoproteolytic behavior (126). It is supposed that cleavage products leave the proteasome mainly via the (opposite) substrate entry but it could be possible to release short peptides through gaps between the a-and b-rings that are still too small to allow substrate access (127).…”

Section: The Degradation Of Oxidized Proteins-a Function Of the 20s Pmentioning

confidence: 99%

The proteasome and its role in the degradation of oxidized proteins

2008

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SummaryThe generation of free radicals and the resulting oxidative modification of cell structures are omnipresent in mammalian cells. This includes the permanent oxidation of proteins leading to the disruption of the protein structure and an impaired functionality. In consequence, these oxidized proteins have to be removed in order to prevent serious metabolic disturbances. The most important cellular proteolytic system responsible for the removal of oxidized proteins is the proteasomal system. For normal functioning, the proteasomal system needs the coordinated interaction of numerous components. This review describes the fundamental functions of the 20S ''core'' proteasome, its regulators, and the roles of the proteasomal system beyond the removal of oxidized proteins in mammalian cells. IUBMBIUBMB Life, 60(11): 743-752, 2008

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“…Proteasomal activity is essential in maintaining low-level basal p21 Cip1/Waf1 protein expression by regulating its degradation. [12][13][14][15] The murine double minute 2 (MDM2) oncogene is amplified and overexpressed in numerous human cancers [16][17][18][19] including Rhabdomyosarcoma (RMS) tumors and cell lines. 20,21 MDM2 negatively regulates p53 transcriptional activity 18,22 and promotes p53 degradation by the proteasome.…”

mentioning

confidence: 99%

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

et al. 2007

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The sphingoplipid ceramide is responsible for a diverse range of biochemical and cellular responses including a putative role in modulating cell cycle progression. Herein, we describe that an accumulation of ceramide, achieved through the exogenous application of C 6 -ceramide or exposure to sphingomyelinase, induces a G 2 arrest in Rhabdomyosarcoma (RMS) cell lines. Utilizing the RMS cell line RD, we show that this G 2 arrest required the rapid induction of p21 Cip1/Waf1 independent of DNA damage. This was followed at later time points (48 h) by the commitment to apoptosis. Apoptosis was prevented by Bcl-2 overexpression, but permitted the maintenance of elevated p21 Cip1/Waf1 protein expression and the stabilization of the G 2 arrest response. Inhibition of p21 Cip1/Waf1 protein synthesis with cyclohexamide (CHX) or silencing of p21 Cip1/Waf1 with siRNA, prevented ceramide-mediated G 2 arrest and the late induction of apoptosis. Further, adopting the recent discovery that murine double minute 2 (MDM2) controls p21 Cip1/Waf1 expression by presenting this CDK inhibitor to the proteasome for degradation, RD cells overexpressing MDM2 abrogated ceramide-mediated p21 Cip1/Waf1 induction, G 2 arrest and the late ensuing apoptosis. Collectively, these data further support the notion that ceramide accumulation can modulate cell cycle progression. Additionally, these observations highlight MDM2 expression and proteasomal activity as key determinants of the cellular response to ceramide accumulation.

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Endoproteolytic Activity of the Proteasome

Cited by 400 publications

References 30 publications

TBP-1 protects the human oncosuppressor p14ARF from proteasomal degradation

TBP-1 protects the human oncosuppressor p14ARF from proteasomal degradation

The proteasome and its role in the degradation of oxidized proteins

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

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