Functional overlap of sequences that activate transcription and signal ubiquitin-mediated proteolysis

Salghetti, Simone E.; Muratani, Masafumi; Wijnen, Herman; Futcher, Bruce; Tansey, William P.

doi:10.1073/pnas.97.7.3118

Cited by 240 publications

(193 citation statements)

References 53 publications

Supporting

Mentioning

183

Contrasting

Order By: Relevance

“…Interestingly, structural predictions obtained with different algorithms reveal that the C-terminal region of ERM may be unstructured or only slightly structured. In some unstable transcription factors, investigators report an overlap between sequences that activate transcription and those that signal degradation, so that the transcriptional activity of these proteins is coupled to their proteolytic destruction (Molinari et al, 1999;Salghetti et al, 2000;Muratani and Tansey, 2003). In ERM, likewise, deletion of the C-terminal domain previously characterized as a transactivation domain (TAD) (Laget et al, 1996) affects both the ability to transactivate and the rate of degradation.…”

Section: Discussionmentioning

confidence: 99%

The 26S proteasome system degrades the ERM transcription factor and regulates its transcription-enhancing activity

et al. 2006

View full text Add to dashboard Cite

ERM is a member of the ETS transcription factor family. High levels of the corresponding mRNA are detected in a variety of human breast cancer cell lines, as well as in aggressive human breast tumors. As ERM protein is almost undetectable in these cells, high degradation of this transcription factor has been postulated. Here we have investigated whether ERM degradation might depend on the proteasome pathway. We show that endogenous and ectopically expressed ERM protein is short-lived protein and undergoes proteasome-dependent degradation. Deletion mutagenesis studies indicate that the 61 C-terminal amino acids of ERM are critical for its proteolysis and serve as a degradation signal. Although ERM conjugates with ubiquitin, this post-translational modification does not depend on the C-terminal domain. We have used an Ets-responsive ICAM-1 reporter plasmid to show that the ubiquitin-proteasome pathway can affect transcriptional function of ERM. Thus, ERM is subject to degradation via the 26S proteasome pathway, and this pathway probably plays an important role in regulating ERM transcriptional activity.

show abstract

Section: Discussionmentioning

confidence: 99%

The 26S proteasome system degrades the ERM transcription factor and regulates its transcription-enhancing activity

et al. 2006

View full text Add to dashboard Cite

show abstract

“…There are many examples of unstable transcription factors in which there is overlap between TAD and degron sequences (Salghetti et al, 2000;Muratani and Tansey, 2003). Such overlap is thought to contribute to the coupling of the activity of transcription factors with their proteasome-mediated destruction and various models have been proposed to describe how activator degradation might limit or stimulate transcription (Salghetti et al, 2000;Lipford and Deshaies, 2003;Muratani and Tansey, 2003;Lipford et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Such overlap is thought to contribute to the coupling of the activity of transcription factors with their proteasome-mediated destruction and various models have been proposed to describe how activator degradation might limit or stimulate transcription (Salghetti et al, 2000;Lipford and Deshaies, 2003;Muratani and Tansey, 2003;Lipford et al, 2005). Thus, degradation might function to limit how long any single activator remains bound at a promoter, facilitating reprogramming of transcriptional patterns, or it might be required to remove spent activators that would otherwise block continued initiation of transcription.…”

Section: Discussionmentioning

confidence: 99%

SCF^Cdc4-mediated Degradation of the Hac1p Transcription Factor Regulates the Unfolded Protein Response inSaccharomyces cerevisiae

Pal

Chan

Helfenbaum

et al. 2007

MBoC

Self Cite

View full text Add to dashboard Cite

The Saccharomyces cerevisiae basic leucine zipper transcription factor Hac1p is synthesized in response to the accumulation of unfolded polypeptides in the lumen of the endoplasmic reticulum (ER), and it is responsible for up-regulation of ϳ5% of all yeast genes, including ER-resident chaperones and protein-folding catalysts. Hac1p is one of the most short-lived yeast proteins, having a half-life of ϳ1.5 min. Here, we have shown that Hac1p harbors a functional PEST degron and that degradation of Hac1p by the proteasome involves the E2 ubiquitin-conjugating enzyme Ubc3/Cdc34p and the SCF Cdc4 E3 complex. Consistent with the known nuclear localization of Cdc4p, rapid degradation of Hac1p requires the presence of a functional nuclear localization sequence, which we demonstrated to involve basic residues in the sequence 29 RKRAKTK 35 . Two-hybrid analysis demonstrated that the PEST-dependent interaction of Hac1p with Cdc4p requires Ser146 and Ser149. Turnover of Hac1p may be dependent on transcription because it is inhibited in cell mutants lacking Srb10 kinase, a component of the SRB/mediator module of the RNA polymerase II holoenzyme. Stabilization of Hac1p by point mutation or deletion, or as the consequence of defects in components of the degradation pathway, results in increased unfolded protein response element-dependent transcription and improved cell viability under ER stress conditions. INTRODUCTIONIn eukaryotic cells, the endoplasmic reticulum (ER) is the portal for newly synthesized proteins destined for all compartments of the exocytic and endocytic pathways as well as for the cell surface and the extracellular space. Transport along the exocytic pathway requires that passenger proteins are correctly folded and assembled (Gething et al., 1986; for review, see Ellgaard and Helenius, 2003), a process that is assisted by molecular chaperones and folding catalysts resident in the ER lumen (for review, see van Anken and Braakman, 2005). The concentrations of these components in the ER are adjusted according to need by the unfolded protein response (UPR; Kozutsumi et al., 1988;Mori et al., 1992; for review, see Kaufman, 1999;Ma and Hendershot, 2001;Patil and Walter, 2001;Schrö der and Kaufman, 2005). The UPR regulates the transcription of ϳ5% of the open reading frames in the Saccharomyces cerevisiae genome, many of which encode proteins with functions involved in diverse processes, including protein translocation, glycosylation, folding and degradation, lipid/inositol metabolism, vesicular trafficking, vacuolar protein sorting, and cell wall biogenesis (Travers et al., 2000).The yeast unfolded protein response (UPR) involves two unique participants, the Ire1p transmembrane receptor kinase/endonuclease (Cox et al., 1993;Mori et al., 1993), and the basic leucine zipper (bZip) transcription factor Hac1p Mori et al., 1996), which transactivates genes bearing UPRE elements (Mori et al., 1992(Mori et al., , 1998Patil and Walter, 2004). HAC1 mRNA is synthesized constitutively as a precursor bearing a 252-nucleotid...

show abstract

“…Another signal for degradation is the transcription activation domain (TAD) itself. It has been reported that VP16 and several other unstable transcription factors such as E2F-1, Jun, Myc, p53, Fos and GCN4 have overlapping TADs and degron signals (60). It has been demonstrated that increasing the number of TADs decreases the half-life of the protein.…”

Section: Ubiquitin-proteasome Pathway and Nhr Transcriptional Regulationmentioning

confidence: 99%

Nuclear hormone receptor degradation and gene transcription: An update

Ismail

Nawaz

2005

IUBMB Life (International Union of Biochemistry and Molecular B

View full text Add to dashboard Cite

SummaryThe ubiquitin-proteasome pathway (UPP) is known to degrade short-lived and misfolded proteins. Its role in cell cycle regulation and signal transduction is well established. However, the importance of the UPP in nuclear hormone receptor-regulated gene transcription is relatively new. Nuclear hormone receptors (NHRs) are degraded by the UPP both in the presence or absence of their cognate ligands. In recent years, it has become evident that NHR degradation and NHR-dependent transcription are interdependent processes. The link between these two processes has become stronger with the discovery of a number of ubiquitin-pathway enzymes and components of the proteasome acting as modulators of NHR function. Also, UPP enzymes and components of the proteasome are recruited to the promoters of NHR-responsive genes. Interestingly both coactivators and corepressors (coregulators) of NHRs are also targeted to the UPP for degradation. Furthermore, additional evidence also indicates that the UPP may be involved in the turnover of transcription complexes, thereby facilitating proper gene transcription. In this review we discuss and provide an update on the role of UPP in NHR-dependent gene regulation. IUBMB Life, 57: 483 -490, 2005

show abstract

Functional overlap of sequences that activate transcription and signal ubiquitin-mediated proteolysis

Cited by 240 publications

References 53 publications

The 26S proteasome system degrades the ERM transcription factor and regulates its transcription-enhancing activity

The 26S proteasome system degrades the ERM transcription factor and regulates its transcription-enhancing activity

SCF^Cdc4-mediated Degradation of the Hac1p Transcription Factor Regulates the Unfolded Protein Response inSaccharomyces cerevisiae

Nuclear hormone receptor degradation and gene transcription: An update

Contact Info

Product

Resources

About

Functional overlap of sequences that activate transcription and signal ubiquitin-mediated proteolysis

Cited by 240 publications

References 53 publications

The 26S proteasome system degrades the ERM transcription factor and regulates its transcription-enhancing activity

The 26S proteasome system degrades the ERM transcription factor and regulates its transcription-enhancing activity

SCFCdc4-mediated Degradation of the Hac1p Transcription Factor Regulates the Unfolded Protein Response inSaccharomyces cerevisiae

Nuclear hormone receptor degradation and gene transcription: An update

Contact Info

Product

Resources

About

SCF^Cdc4-mediated Degradation of the Hac1p Transcription Factor Regulates the Unfolded Protein Response inSaccharomyces cerevisiae