The proteasome and its regulatory roles in gene expression

Kwak, Jaechan; Workman, Jerry L.; Lee, Daeyoup

doi:10.1016/j.bbagrm.2010.08.001

Cited by 39 publications

(38 citation statements)

References 142 publications

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“…Sox4 proteasomal degradation appeared most prominent in the nucleus, but also cytosol-localized Sox4 mutants were sensitive to proteasomal degradation. Both nuclear and cytosolic proteasomal activity has been shown critical for regulation of multiple transcription factors by ubiquitin-and non-ubiquitin-dependent mechanisms (Kwak et al, 2010). Proteasome subunits diffuse throughout the cell during mitoses and the proportion of nuclear proteasomes are correlated to cellular proliferation rates, suggesting that Sox4 degradation and function may be regulated during various stages of the cell cycle (Reits et al, 1997;Kruger et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

et al. 2011

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The transcription factor Sox4 is aberrantly expressed in many human tumors and can modulate tumorigenesis and metastases of murine tumors in vivo. However, mechanisms that control Sox4 function remain poorly defined. It has recently been observed that DNA damage increases Sox4 protein expression independently of Sox4 mRNA levels, suggesting an as yet undefined post-transcriptional mechanism regulating Sox4 expression and functionality. Here, we show that Sox4 protein is rapidly degraded by the proteasome as indicated by pharmacological inhibition with Mg132 and epoxymycin. Sox4 half-life was found to be less than 1 h as evident by inhibition of protein synthesis using cycloheximide. Ectopic expression of Sox4 deletion mutants revealed that the C-terminal 33 residues of Sox4 were critical in modulating its degradation in a polyubiquitin-independent manner. Syntenin, a Sox4 binding partner, associates with this domain and was found to stabilize Sox4 expression. Syntenin-induced stabilization of Sox4 correlated with Sox4-syntenin relocalization to the nucleus, where both proteins accumulate. Syntenin overexpression or knockdown in human tumor cell lines was found to reciprocally modulate Sox4 protein expression and transcriptional activity implicating its role as a regulator of Sox4. Taken together, our data demonstrate that the Sox4 C-terminal domain regulates polyubiquitinindependent proteasomal degradation of Sox4 that can be modulated by interaction with syntenin. As aberrant Sox4 expression has been found associated with many human cancers, modulation of Sox4 proteasomal degradation may impact oncogenesis and metastatic properties of tumors.

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Section: Discussionmentioning

confidence: 99%

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

et al. 2011

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“…3). These stages include: initiation of RNA transcription by transcription factors and their associated co-activators, which recruit the transcriptional machinery (RNA polymerase II/general transcription factors) to gene promoters [reviewed elsewhere (71)]; RNA elongation, which requires chromatin remodeling through the removal and redeposition of histone proteins; and RNA processing and nuclear export [reviewed elsewhere (72)]. …”

Section: Ubr5 and Regulation Of Gene Expressionmentioning

confidence: 99%

Functional Roles of the E3 Ubiquitin Ligase UBR5 in Cancer

Shearer

Iconomou

Watts

et al. 2015

Molecular Cancer Research

107

141

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The Ubiquitin-Proteasome System (UPS) is an important regulator of cell signaling and proteostasis, which are essential to a variety of cellular processes. The UPS is disrupted in many diseases including cancer, and targeting the UPS for cancer therapy is gaining wide interest. E3 ubiquitin ligases occupy a key position in the hierarchical UPS enzymatic cascade, largely responsible for determining substrate specificity and ubiquitin (Ub) chain topology. The E3 ligase UBR5 (aka EDD1) is emerging as a key regulator of the UPS in cancer and development. UBR5 expression is deregulated in many cancer types and UBR5 is frequently mutated in mantle cell lymphoma. UBR5 is highly conserved in metazoans, has unique structural features, and has been implicated in regulation of DNA damage response, metabolism, transcription, and apoptosis. Hence, UBR5 is a key regulator of cell signaling relevant to broad areas of cancer biology. However, the mechanism by which UBR5 may contribute to tumor initiation and progression remains poorly defined. This review synthesizes emerging insights from genetics, biochemistry, and cell biology to inform our understanding of UBR5 in cancer. These molecular insights indicate a role for UBR5 in integrating/coordinating various cellular signaling pathways. Finally, we discuss outstanding questions in UBR5 biology and highlight the need to systematically characterize substrates, and address limitations in current animal models, to better define the role of UBR5 in cancer.

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“…The 26S proteasome also plays roles in transcription initiation by controlling the location and quantity of available transcription factors [70]. The 26S proteasome is composed of three distinct sub-complexes: the 19S regulatory particle (RP) lid, the 19S RP base, and the 20S catalytic particle (CP) [71].…”

Section: The 26s Proteasome: Degrader Of Proteinsmentioning

confidence: 99%

A Role for Histone Chaperones in Regulating RNA Polymerase II

Osborn¹,

Greer²

2015

ABC

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Transcription is a highly regulated cellular process in which dysfunction leads to disease. One level of regulation is chromatin structure which protects promoters from transcription factor binding. To circumvent this blockade, histone chaperones aid in displacement of nucleosomes. In particular, the histone chaperone complex HUCA, consisting of Hira, Ubn1, Cabin1, and ASF1a, replaces histone variant H3.1 with H3.3 in front of actively transcribing RNA Polymerase II (RNAPII). The 26S proteasome is a major degrader of proteins within the cell and plays both proteolytic and nonproteolytic roles in transcriptional regulation. One major role is the degradation of irreversibly arrested RNAPII. Several interactions between HUCA, the 26S proteasome, and RNAPII have been characterized individually; we now present observations from our lab and others which directly associate elongating RNAPII with the degradation machinery through observations of involvement with the HUCA complex. Our short report presents these ideas and discusses their importance in transcriptional regulation as well as implications in disease manifestation.

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The proteasome and its regulatory roles in gene expression

Cited by 39 publications

References 142 publications

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

Functional Roles of the E3 Ubiquitin Ligase UBR5 in Cancer

A Role for Histone Chaperones in Regulating RNA Polymerase II

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