Identification of Novel Targets of MYC Whose Transcription Requires the Essential MbII Domain

Zhang, Xiaoyong; DeSalle, Lauren M; McMahon, Steven B.

doi:10.4161/cc.5.3.2409

Cited by 10 publications

(11 citation statements)

References 53 publications

(64 reference statements)

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“…These studies have consistently identified several thousand loci as being MYC responsive (31). The overall strategy for the screen and initial validation of MTA1 as an important target have been described previously (43,44). Expression profiling demonstrated that activation of the wild-type MYC (MYC/ER) allele in primary human fibroblasts caused a consistent 2-to 3-fold induction of BAG1 transcript levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of the Single Downstream Target BAG1 Activates the Latent Apoptotic Potential of MYC

Zhang¹,

Pfeiffer²,

Mellert³

et al. 2011

Molecular and Cellular Biology

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Aberrant MYC expression is a common oncogenic event in human cancer. Paradoxically, MYC can either drive cell cycle progression or induce apoptosis. The latent ability of MYC to induce apoptosis has been termed "intrinsic tumor suppressor activity," and reactivating this apoptotic function in tumors is widely considered a valuable therapeutic goal. As a transcription factor, MYC controls the expression of many downstream targets, and for the majority of these, it remains unclear whether or not they play direct roles in MYC function. To identify the subset of genes specifically required for biological activity, we conducted a screen for functionally important MYC targets and identified BAG1, which encodes a prosurvival chaperone protein. Expression of BAG1 is regulated by MYC in both a mouse model of breast cancer and transformed human cells. Remarkably, BAG1 induction is essential for protecting cells from MYC-induced apoptosis. Ultimately, the synthetic lethality we have identified between MYC overexpression and BAG1 inhibition establishes a new pathway that might be exploited to reactivate the latent apoptotic potential of MYC as a cancer therapy.

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Section: Resultsmentioning

confidence: 99%

“…MIGR1-based retroviral expression cassettes were generated by insertion of the human c-myc/estrogen receptor ligand binding domain fusion cassette (43). The MYC⌬MbII/ER mutant was generated by deletion of amino acids 110 to 150 by use of the QuikChange mutagenesis protocol (Stratagene).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of the Single Downstream Target BAG1 Activates the Latent Apoptotic Potential of MYC

Zhang¹,

Pfeiffer²,

Mellert³

et al. 2011

Molecular and Cellular Biology

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“…These results suggest that L11 attenuates c-Myc-mediated gene transcription via interfering with the recruitment of the TRRAP co-activator to c-Myc target gene promoters, 61 further emphasizing the central importance of the MB II region in c-Myc-mediated transactivation and its regulation by c-Myc regulators. 39,75 Interestingly, the inhibitory effect of L11 on c-Myc activity resembles the regulation of c-Myc by ARF. [76][77][78] Similarly, ARF binds to the MB II 79 and suppresses c-Myc activity, although it has not been tested if ARF may do so by interfering with the TRRAP recruitment and subsequent histone acetylation.…”

Section: Feedback Inhibition Of C-myc Activity By L11mentioning

confidence: 96%

Feedback Regulation of c-Myc by Ribosomal Protein L11

Dai¹,

Sears²,

Lu³

2007

Cell Cycle

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Several ribosomal proteins including L11 have been shown to activate p53 by inhibiting oncoprotein MDM2, leading to inhibition of cell cycle progression. Our recent study showed that L11 also inhibits oncoprotein c-Myc. Overexpression of L11 inhibits c-Myc-induced transcription and cell proliferation, while reduction of endogenous L11 increases these c-Myc activities. Interestingly, L11 is a transcriptional target of c-Myc, thus forming a negative feedback loop. We further showed that L11 competes with co-activator TRRAP for binding to c-Myc through the Myc box II (MB II) and reduces histone H4 acetylation at c-Myc target gene promoters. In addition, L11 appears to regulate c-Myc levels. Knocking down L11 markedly increases the mRNA and protein levels of endogenous c-Myc. These results suggest that L11 also inhibits cell cycle progression by regulating the c-Myc pathway. Here we further discuss the implications of this regulation and questions that this finding raises.

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“…Second, these targets may serve as points of therapeutic intervention in the face of our historic inability to target MYC directly. To address this knowledge gap, we previously performed a structure-function based screen to identify MYC targets linked to malignant transformation [4]. This screen identified a subset of ~20 MYC targets as specifically correlated with transformation [4].…”

Section: Introductionmentioning

confidence: 99%

Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer

et al. 2016

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Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production. Fortuitously, MYC-dependent tumor cell death can be induced by inhibiting the mitochondrial gene expression pathway using a variety of strategies, including treatment with FDA-approved antibiotics. In vivo studies using a mouse model of Burkitt's Lymphoma provide pre-clinical evidence that these antibiotics can successfully block progression of MYC-dependent tumors.

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Identification of Novel Targets of MYC Whose Transcription Requires the Essential MbII Domain

Cited by 10 publications

References 53 publications

Inhibition of the Single Downstream Target BAG1 Activates the Latent Apoptotic Potential of MYC

Inhibition of the Single Downstream Target BAG1 Activates the Latent Apoptotic Potential of MYC

Feedback Regulation of c-Myc by Ribosomal Protein L11

Multi-focal control of mitochondrial gene expression by oncogenic MYC provides potential therapeutic targets in cancer

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