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The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy.

Lukey MJ, Greene KS, Erickson JW, Wilson KF, Cerione RA - Nat Commun (2016)

Bottom Line: We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression.Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity.These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.

ABSTRACT
Many transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes. These metabolic adaptations, which accompany tumorigenesis, are driven by oncogenic signals. Here we report that the transcription factor c-Jun, product of the proto-oncogene JUN, is a key regulator of mitochondrial glutaminase (GLS) levels. Activation of c-Jun downstream of oncogenic Rho GTPase signalling leads to elevated GLS gene expression and glutaminase activity. In human breast cancer cells, GLS protein levels and sensitivity to GLS inhibition correlate strongly with c-Jun levels. We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression. Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity. These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.

No MeSH data available.


Related in: MedlinePlus

c-Jun coordinates cell cycle progression with metabolic reprogramming.Diagram summarizes the coordinated regulation of cell proliferation by c-Jun. Transcriptional activity of c-Jun can be enhanced by activating phosphorylations downstream of mitogenic signalling pathways, including those mediated by the Rho family of GTPases. c-Jun can also be upregulated by amplification or increased expression of the JUN proto-oncogene. A key role for c-Jun is to drive cell cycle progression, which is achieved through transcriptional repression of cell cycle inhibitors and transcriptional activation of cell cycle progression machinery. In this study, we report that c-Jun also controls metabolic reprogramming to support proliferation, by upregulating GLS expression and thereby stimulating delivery of glutamine-derived carbon into the TCA cycle.
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f8: c-Jun coordinates cell cycle progression with metabolic reprogramming.Diagram summarizes the coordinated regulation of cell proliferation by c-Jun. Transcriptional activity of c-Jun can be enhanced by activating phosphorylations downstream of mitogenic signalling pathways, including those mediated by the Rho family of GTPases. c-Jun can also be upregulated by amplification or increased expression of the JUN proto-oncogene. A key role for c-Jun is to drive cell cycle progression, which is achieved through transcriptional repression of cell cycle inhibitors and transcriptional activation of cell cycle progression machinery. In this study, we report that c-Jun also controls metabolic reprogramming to support proliferation, by upregulating GLS expression and thereby stimulating delivery of glutamine-derived carbon into the TCA cycle.

Mentions: When taken together, these findings provide a biological rationale for the positive regulation of GLS by c-Jun that we describe. In order for sustained proliferation to occur, signalling to the cell cycle machinery must be coordinated with reprogramming of cellular metabolism to support biomass accumulation. By simultaneously driving cell cycle progression and upregulating GLS expression, c-Jun promotes cell proliferation and also activates TCA cycle anaplerosis to replenish metabolites that have been directed to biosynthetic pathways (Fig. 8). Notably, two other reported regulators of GLS expression are involved in cell cycle control. The Rb protein prevents G1 to S phase progression58, and loss of this tumour suppressor leads to upregulation of GLS41. Similarly, the oncogenic transcription factor c-Myc promotes G1 to S phase transition, and is a positive regulator of GLS expression2223.


The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy.

Lukey MJ, Greene KS, Erickson JW, Wilson KF, Cerione RA - Nat Commun (2016)

c-Jun coordinates cell cycle progression with metabolic reprogramming.Diagram summarizes the coordinated regulation of cell proliferation by c-Jun. Transcriptional activity of c-Jun can be enhanced by activating phosphorylations downstream of mitogenic signalling pathways, including those mediated by the Rho family of GTPases. c-Jun can also be upregulated by amplification or increased expression of the JUN proto-oncogene. A key role for c-Jun is to drive cell cycle progression, which is achieved through transcriptional repression of cell cycle inhibitors and transcriptional activation of cell cycle progression machinery. In this study, we report that c-Jun also controls metabolic reprogramming to support proliferation, by upregulating GLS expression and thereby stimulating delivery of glutamine-derived carbon into the TCA cycle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837472&req=5

f8: c-Jun coordinates cell cycle progression with metabolic reprogramming.Diagram summarizes the coordinated regulation of cell proliferation by c-Jun. Transcriptional activity of c-Jun can be enhanced by activating phosphorylations downstream of mitogenic signalling pathways, including those mediated by the Rho family of GTPases. c-Jun can also be upregulated by amplification or increased expression of the JUN proto-oncogene. A key role for c-Jun is to drive cell cycle progression, which is achieved through transcriptional repression of cell cycle inhibitors and transcriptional activation of cell cycle progression machinery. In this study, we report that c-Jun also controls metabolic reprogramming to support proliferation, by upregulating GLS expression and thereby stimulating delivery of glutamine-derived carbon into the TCA cycle.
Mentions: When taken together, these findings provide a biological rationale for the positive regulation of GLS by c-Jun that we describe. In order for sustained proliferation to occur, signalling to the cell cycle machinery must be coordinated with reprogramming of cellular metabolism to support biomass accumulation. By simultaneously driving cell cycle progression and upregulating GLS expression, c-Jun promotes cell proliferation and also activates TCA cycle anaplerosis to replenish metabolites that have been directed to biosynthetic pathways (Fig. 8). Notably, two other reported regulators of GLS expression are involved in cell cycle control. The Rb protein prevents G1 to S phase progression58, and loss of this tumour suppressor leads to upregulation of GLS41. Similarly, the oncogenic transcription factor c-Myc promotes G1 to S phase transition, and is a positive regulator of GLS expression2223.

Bottom Line: We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression.Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity.These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.

ABSTRACT
Many transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes. These metabolic adaptations, which accompany tumorigenesis, are driven by oncogenic signals. Here we report that the transcription factor c-Jun, product of the proto-oncogene JUN, is a key regulator of mitochondrial glutaminase (GLS) levels. Activation of c-Jun downstream of oncogenic Rho GTPase signalling leads to elevated GLS gene expression and glutaminase activity. In human breast cancer cells, GLS protein levels and sensitivity to GLS inhibition correlate strongly with c-Jun levels. We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression. Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity. These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.

No MeSH data available.


Related in: MedlinePlus