EGR1 drives cell proliferation by directly stimulating TFEB transcription in response to starvation
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ABSTRACT:
PROVIDER: PRJNA862890 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20670901.fastq.gz | Fastqsanger.gz | |||
| SRR20671201.fastq.gz | Fastqsanger.gz | |||
| SRR20671203.fastq.gz | Fastqsanger.gz | |||
| SRR20671205.fastq.gz | Fastqsanger.gz | |||
| SRR20671207.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
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Project description:Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
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Project description:Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
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Project description:Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
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Project description:Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
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Project description:Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function1. The recent identification of ER-phagy receptors has shed light on the molecular mechanism underlining this process; however, the signaling pathways regulating ER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3 - master regulators of lysosomal biogenesis and autophagy2- control ER-phagy by inducing the expression of the ER-phagy receptor FAM134B. The TFEB/TFE3-FAM134B axis promotes ER-phagy activation upon prolonged starvation. In addition, we discovered that this pathway is activated in chondrocytes by FGF signaling, a critical regulator of cell differentiation 3. FGF signaling induces a JNK-dependent proteasomal degradation of the insulin receptor substrate 1, which inhibits the insulin-PI3K-PKB/Akt-mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and FAM134B induction. Consistent with a role of the TFEB/TFE3-FAM134B axis in chondrocytes, FAM134B knock-down impairs cartilage growth and mineralization in medaka fish. This study identifies a new signaling pathway that allows ER-phagy to respond to both metabolic and developmental cues.
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Project description:Transcription factor EB (TFEB), well characterized as a master regulator of autophagy and lysosomal biogenesis, is translocated to the nucleus and activated by varieties of cellular stresses including starvation and lysosomal damage. However, compared to the starvation condition, the molecular mechanism of TFEB activation by other stress conditions is poorly understood. Previously, we have shown that TFEB activation during lysosomal damage but not starvation condition depends on a subset of autophagy regulators, collectively called ATG conjugation system, whose function is essential for the lipidation of ATG8 proteins. In this study, by time-lapse imaging, we newly identified the presence of ATG conjugation system -independent TFEB regulation which precedes the ATG conjugation system-dependent regulation, designated mode I and mode II, respectively. Consistent with the presence of different modes, our time course transcriptome analysis revealed two different sets of TFEB downstream. Comprehensive interactome analysis of TFEB and subsequent functional screening identified unique regulars of TFEB in each mode: APEX1 for Mode I and CCT7 and/or TRIP6 for Mode II, respectively. APEX1 interacted with TFEB and was required for its protein stability in a manner independent of ATG conjugation system. On the other hand, both CCT7 and TRIP6 were accumulated on lysosomes during lysosomal damage and interacted with TFEB mainly in ATG conjugation system deficient cells, presumably blocking TFEB nuclear translocation. Moreover, we further revealed that TFEB regulatory mechanisms by other cellular stresses such as oxidative stress, proteasome inhibition, mitochondria depolarization, and DNA damage can be classified into either APEX1-mediated Mode I or TRIP6-mediated Mode II. Our results pave the way for a unified understanding TFEB regulatory mechanisms from the perspective of ATG conjugation system under varieties of cellular stresses.
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