Ubiquitin-Dependent Turnover of MYC Antagonizes MYC/PAF1C Complex Accumulation to Drive Transcriptional Elongation

Jaenicke, Laura A.; Eyß, Björn von; Carstensen, Anne; Wolf, Elmar; Xu, Wen-Shan; Greifenberg, Ann Katrin; Geyer, Matthias; Eilers, Martin; Popov, Nikita

doi:10.1016/j.molcel.2015.11.007

Cited by 93 publications

(118 citation statements)

References 32 publications

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…Alternatively, recruitment may be more indirect; for example, one of the best validated effector functions of C-MYC is the interaction of MYCBoxII with the TRRAP protein, a scaffold of the NuA4 histone acetylase complex, which has multiple roles in gene expression and in maintaining genome stability (134). C-MYC-induced histone acetylation in turn can recruit p-TEFB via the BRD4 protein (135). Intriguingly, NuA4 has recently been implicated in elongation by RNAPII (136), suggesting that recruitment of NuA4 to core promoters may contribute to MYC-dependent pauserelease.…”

Section: N-myc-dependent Transcriptionmentioning

confidence: 99%

See 1 more Smart Citation

The Expanding World of N-MYC–Driven Tumors

2018

Self Cite

View full text Add to dashboard Cite

Enhanced and deregulated expression of N-MYC, a member of the MYC family of transcription factors, drives the development of multiple tumors, including tumors of the nervous and hematologic systems and neuroendocrine tumors in other organs. This review summarizes the cell-of-origin, biological features, associated signaling pathways, and current treatment strategies for N-MYC-driven tumors. We also highlight biological differences within specifi c tumor types that are driven by the different MYC proteins.Signifi cance: N-MYC is a driver of multiple tumor types that are derived through a mechanism that involves direct differentiation within the same lineage (e.g., in the case of neuroblastoma, medulloblastoma, and acute myeloid leukemia) and is often associated with a poor prognosis. Emerging data suggest that N-MYC also drives other tumor types through a mechanism that promotes a lineage switch and that this switch may be exploited for therapeutic purposes. Cancer Discov; 8(2);

show abstract

Section: N-myc-dependent Transcriptionmentioning

confidence: 99%

“…The efficacy of targeting BRD4 in targeting N-MYCdriven tumors may also be due to a role of BRD4 in MYCdriven transcription, as BRD4 can be recruited by MYC proteins to core promoters (135). Although BRD4 has kinase activity itself, it is best known for its role in recruiting p-TEFB and CDK9 to core promoters.…”

Section: Targeting N-myc Transcriptional Functionmentioning

confidence: 99%

The Expanding World of N-MYC–Driven Tumors

2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…It was recently shown that the proteasomal turnover of c-MYC is required for full activity. Lysine-mutated c-MYC failed to induce tumorigenesis as inhibitory complexes could not be removed during target gene activation (58), whereas other TFs are independent of ongoing degradation for their transcriptional activity (60). Surprisingly, EWS-FLI1 induced distinct behavior in three subgroups of target genes.…”

Section: Ews-fli1 Degradation Is Mediated By One Lysine Residuementioning

confidence: 98%

“…Most interestingly, the activity of TFs can be influenced by their own turnover as shown for estrogen receptor ␣ or c-MYC (58,59). It was recently shown that the proteasomal turnover of c-MYC is required for full activity.…”

Section: Ews-fli1 Degradation Is Mediated By One Lysine Residuementioning

confidence: 99%

Proteasomal Degradation of the EWS-FLI1 Fusion Protein Is Regulated by a Single Lysine Residue

Gierisch

Pfistner

Lopez-Garcia

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by George DeMartinoEHere, we identify the EWS-FLI1 protein as a substrate of the ubiquitin-proteasome system with a characteristic polyubiquitination pattern. Using a global protein stability approach, we determined the half-life of EWS-FLI1 to lie between 2 and 4 h, whereas full-length EWSR1 and FLI1 were more stable. By mass spectrometry, we identified two ubiquitin acceptor lysine residues of which only mutation of Lys-380 in the ETS domain of the FLI1 part abolished EWS-FLI1 ubiquitination and stabilized the protein posttranslationally. Expression of this highly stable mutant protein in Ewing cells while simultaneously depleting the endogenous wild type protein differentially modulates two subgroups of target genes to be either EWS-FLI1 protein-dependent or turnover-dependent. The majority of target genes are in an unaltered state and cannot be further activated. Our study provides novel insights into EWS-FLI1 turnover, a critical pathway in Ewing sarcoma pathogenesis, and lays new ground to develop novel therapeutic strategies in Ewing sarcoma. E-26 transformation-specific (ETS)2 family members are strong activators or repressors of transcription with a highly conserved ETS domain (1-3). ETS transcription factors (TFs) bind most commonly in complexes to a GGA core region to mediate gene expression (4, 5). Their main biological functions include regulation of differentiation, lineage determination of the hematopoietic system, and control of angiogenesis (6, 7). Most of the ETS family members have oncogenic potential because truncated or overexpressed ETS proteins have been linked to several cancer entities (8 -11). ERG and ETV1 are frequently fused to the TMPRSS2 promoter in prostate cancer, whereas ETV1 and ETV6 are implicated in leukemia (12, 13). Like other aberrant fusion proteins, they act as drivers of uncontrolled cell growth and survival (14, 15). However, most TFs do not harbor an enzymatic pocket and are therefore difficult to target directly. Novel strategies that uncover vulnerable sites in TFs are urgently needed to develop novel targeted therapies (16).Ewing sarcoma is a rare pediatric bone and soft tissue tumor with an aggressive behavior and prevalence to metastasize (17,18). Its main genetic abnormalities are EWS-ETS rearrangements, among them most commonly the EWS gene on chromosome 22 fused to FLI1 on chromosome 11, which results in expression of the chimeric transcription factor . Continuous expression of the fusion protein is crucial for tumor formation, progression, and maintenance (22, 23), and its down-regulation inhibits proliferation and reduces tumor cell growth (24 -26). EWS-FLI1 is thought to function mainly as a modulator to activate and repress a wide range of target genes but also as a regulator of splicing processes or as a component of large interaction networks (27-31). However, inhibition of a single downstream target gene has not been proven effective yet for Ewing sarcoma therapy.The turnover of most intracellular proteins is mediated via the ubiquitin-proteasome ...

show abstract

“…1 MYC binds with the highest affinity to specific DNA sequences, called E-boxes (CACGTG), as a heterodimeric complex with its partner protein MAX, leading to transactivation of its target genes by recruitment of several cofactors, such as TRRAP and associated histone acetyltransferases. 2,3 Given MYC's large number of binding sites and its many target genes, it has been very difficult to assign specific target genes to MYC's oncogenic role, even though it is clear that high MYC activity is predictive in terms of prognosis. 4 Consequently, high MYC activity typically leads to a poor survival prognosis in a multitude of tumor entities.…”

Section: Introductionmentioning

confidence: 99%

TEAD activity is restrained by MYC and stratifies human breast cancer subtypes

et al. 2016

Self Cite

View full text Add to dashboard Cite

c-Myc (MYC) is an oncogenic transcription factor that is commonly overexpressed in a wide variety of human tumors. In breast cancer, MYC has recently been linked to the triple-negative subtype, a subtype that lacks any targeted therapy. Previously, we demonstrated that MYC behaves as a potent repressor of YAP and TAZ, 2 transcriptional coactivators that function as downstream transducers of the Hippo pathway. In this previous study, MYC repressed YAP/TAZ not only in primary breast epithelial cells but also in mouse models of triplenegative tumors. Here, we extend our previous bioinformatic and experimental analyses and demonstrate that MYC deregulation in primary breast epithelial cells leads to a robust repression of TEAD transcription factor activity, the transcription factor family mainly responsible for YAP/TAZ recruitment. Surprisingly, we find that MYC and TEAD activity is able to stratify different breast cancer subtypes in large panels of breast cancer patients. Thus, a deep understanding of the MYC-YAP/TAZ circuitry might yield new insights into the establishment and maintenance of specific breast cancer subtypes.

show abstract

Ubiquitin-Dependent Turnover of MYC Antagonizes MYC/PAF1C Complex Accumulation to Drive Transcriptional Elongation

Cited by 93 publications

References 32 publications

The Expanding World of N-MYC–Driven Tumors

The Expanding World of N-MYC–Driven Tumors

Proteasomal Degradation of the EWS-FLI1 Fusion Protein Is Regulated by a Single Lysine Residue

TEAD activity is restrained by MYC and stratifies human breast cancer subtypes

Contact Info

Product

Resources

About