Abstract 3160: A redox-sensitive PEST sequence regulates Nrf2 degradation through proteasome pathway

Signal-induced degradation of I(kappa)B(alpha): association with NF-kappaB and the PEST sequence in I(kappa)B(alpha) are not required.

Molecular and Cellular Biology ◽

10.1128/mcb.16.11.6037 ◽

1996 ◽

Vol 16 (11) ◽

pp. 6037-6045 ◽

Cited By ~ 65

Author(s):

D J Van Antwerp ◽

I M Verma

Keyword(s):

Deletion Mutant ◽

Nf Kappa B ◽

Pest Sequence ◽

Ubiquitin Proteasome Pathway ◽

I Kappa B Alpha ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Nf Kappab ◽

Carboxy Terminal

Signal-induced degradation of I(kappa)B(alpha) via the ubiquitin-proteasome pathway requires phosphorylation on residues serine 32 and serine 36 followed by ubiquitination on lysines 21 and 22. We investigated the role of other regions of I(kappa)B(alpha) which may be involved in its degradation. Here we report that the carboxy-terminal PEST sequence is not required for I(kappa)B(alpha) signal-induced degradation. However, removal of the PEST sequence stabilizes free I(kappa)B(alpha) in unstimulated cells. We further report that a PEST deletion mutant does not associate well with NF-(kappa)B proteins but is degraded in response to signal. Therefore, we conclude that both association with NF-(kappa)B and a PEST sequence are not required for signal-induced I(kappa)B(alpha) degradation. Additionally, the PEST sequence may be required for constitutive turnover of free I(kappa)B(alpha).

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Proteasome inhibitors as therapeutics

Essays in Biochemistry ◽

10.1042/bse0410205 ◽

2005 ◽

Vol 41 ◽

pp. 205-218

Author(s):

Constantine S. Mitsiades ◽

Nicholas Mitsiades ◽

Teru Hideshima ◽

Paul G. Richardson ◽

Kenneth C. Anderson

Keyword(s):

Multiple Myeloma ◽

Drug Class ◽

Proteasome Inhibitors ◽

Cell Cycle Regulators ◽

Current State ◽

Intracellular Mechanism ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Hodgkin's Lymphomas ◽

Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

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Role of molecular chaperones in steroid receptor action

Essays in Biochemistry ◽

10.1042/bse0400041 ◽

2004 ◽

Vol 40 ◽

pp. 41-58 ◽

Cited By ~ 149

Author(s):

William B Pratt ◽

Mario D Galigniana ◽

Yoshihiro Morishima ◽

Patrick J M Murphy

Keyword(s):

Transcriptional Activation ◽

Protein Trafficking ◽

Steroid Receptors ◽

Transcriptional Regulatory ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Receptor Action ◽

Binding Cleft ◽

Hsp 90

Unliganded steroid receptors are assembled into heterocomplexes with heat-shock protein (hsp) 90 by a multiprotein chaperone machinery. In addition to binding the receptors at the chaperone site, hsp90 binds cofactors at other sites that are part of the assembly machinery, as well as immunophilins that connect the assembled receptor-hsp90 heterocomplexes to a protein trafficking pathway. The hsp90-/hsp70-based chaperone machinery interacts with the unliganded glucocorticoid receptor to open the steroid-binding cleft to access by a steroid, and the machinery interacts in very dynamic fashion with the liganded, transformed receptor to facilitate its translocation along microtubular highways to the nucleus. In the nucleus, the chaperone machinery interacts with the receptor in transcriptional regulatory complexes after hormone dissociation to release the receptor and terminate transcriptional activation. By forming heterocomplexes with hsp90, the chaperone machinery stabilizes the receptor to degradation by the ubiquitin-proteasome pathway of proteolysis.

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