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Active Creb3L1 can upregulate secretory pathway genes in HeLa cells

ABSTRACT: Abstract: Secretion occurs in all cells, with relatively low levels in most cells and extremely high levels in specialized secretory cells, such as those of the pancreas, salivary and mammary glands. Here, we report that the CrebA/Creb3-like family of bZip transcription factors functions to upregulate expression of both the general protein machinery required in all cells for secretion and of cell-type specific secreted proteins. Drosophila CrebA directly binds the enhancers of secretory pathway genes and is both necessary and sufficient to activate expression of every secretory pathway component gene examined thus far. Microarray profiling reveals that CrebA also upregulates expression of genes encoding cell type specific secreted components. Finally, we find that the human CrebA orthologues, Creb3L1 and Creb3L2, have the ability to upregulate the secretory pathway in non-secretory cell types. Goals: Creb3L1 is the closest related human orthologue of Drosophila CrebA. CrebA is required to upregulate genes encoding the protein machinery and cargo in specialized secretory cells. To determine if the human orthologues of CrebA, Creb3L1 and Creb3L2, perform the same function, we expressed the truncated active form of Creb3L1 in non-secretory HeLa cells. We then performed microarray experiments and found that active Creb3L1 is sufficient to upregulate genes encoding the protein machinery of the secretory pathway, as observed with Drosophila CrebA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE23334 | GEO | 2010/10/18

SECONDARY ACCESSION(S): PRJNA133299

REPOSITORIES: GEO

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Active Creb3L1 can upregulate secretory pathway genes in HeLa cells

Project description:Abstract: Secretion occurs in all cells, with relatively low levels in most cells and extremely high levels in specialized secretory cells, such as those of the pancreas, salivary and mammary glands. Here, we report that the CrebA/Creb3-like family of bZip transcription factors functions to upregulate expression of both the general protein machinery required in all cells for secretion and of cell-type specific secreted proteins. Drosophila CrebA directly binds the enhancers of secretory pathway genes and is both necessary and sufficient to activate expression of every secretory pathway component gene examined thus far. Microarray profiling reveals that CrebA also upregulates expression of genes encoding cell type specific secreted components. Finally, we find that the human CrebA orthologues, Creb3L1 and Creb3L2, have the ability to upregulate the secretory pathway in non-secretory cell types. Goals: Creb3L1 is the closest related human orthologue of Drosophila CrebA. CrebA is required to upregulate genes encoding the protein machinery and cargo in specialized secretory cells. To determine if the human orthologues of CrebA, Creb3L1 and Creb3L2, perform the same function, we expressed the truncated active form of Creb3L1 in non-secretory HeLa cells. We then performed microarray experiments and found that active Creb3L1 is sufficient to upregulate genes encoding the protein machinery of the secretory pathway, as observed with Drosophila CrebA. HeLa cells were transiently co-transfected with truncated Creb3L1 (Creb3L1 T) and GFP. Following 20 hours in culture, GFP positive cells were isolated by FACS and RNA was extracted using the Rneasy kit (Qiagen). As a control, mock transfected cells were also subjected to cell sorting and RNA was extracted using the same protocols. At least three replicates were obtained for each group.

2010-10-18 | E-GEOD-23334 | biostudies-arrayexpress

The CrebA/Creb3-like transcription factors are major and direct regulators of secretory capacity

2010-10-18 | E-GEOD-23349 | biostudies-arrayexpress

CrebA is a major and direct regulator of secretory pathway gene expression

Project description:Abstract: Secretion occurs in all cells, with relatively low levels in most cells and extremely high levels in specialized secretory cells, such as those of the pancreas, salivary and mammary glands. Here, we report that the CrebA/Creb3-like family of bZip transcription factors functions to upregulate expression of both the general protein machinery required in all cells for secretion and of cell-type specific secreted proteins. Drosophila CrebA directly binds the enhancers of secretory pathway genes and is both necessary and sufficient to activate expression of every secretory pathway component gene examined thus far. Microarray profiling reveals that CrebA also upregulates expression of genes encoding cell type specific secreted components. Finally, we find that the human CrebA orthologues, Creb3L1 and Creb3L2, have the ability to upregulate the secretory pathway in non-secretory cell types. Goals: The goals of the microarray experiments were to identify additional targets of the CrebA transcription factor to learn the range of genes regulated by this transcription factor during embryogenesis. Previous work had indicated that CrebA upregulates the protein machinery of the early secretory pathway. Our new data now shows that in addition to the protein machinery, CrebA also upregulates genes encoding the protein cargo that is secreted from specialized secretory organs. RNA was isolated from stage 11-15 wild type Drosophila embryos and compared to RNA from CrebA null mutant embryos of the same age; all samples were hybridized to the Drosophila Genome 2.0 Affymetrix array. Three individual replicates were obtained for each sample.

2010-10-18 | E-GEOD-23346 | biostudies-arrayexpress

The CrebA/Creb3-like transcription factors are major and direct regulators of secretory capacity

2010-10-18 | GSE23349 | GEO

CrebA is a major and direct regulator of secretory pathway gene expression

Project description:Abstract: Secretion occurs in all cells, with relatively low levels in most cells and extremely high levels in specialized secretory cells, such as those of the pancreas, salivary and mammary glands. Here, we report that the CrebA/Creb3-like family of bZip transcription factors functions to upregulate expression of both the general protein machinery required in all cells for secretion and of cell-type specific secreted proteins. Drosophila CrebA directly binds the enhancers of secretory pathway genes and is both necessary and sufficient to activate expression of every secretory pathway component gene examined thus far. Microarray profiling reveals that CrebA also upregulates expression of genes encoding cell type specific secreted components. Finally, we find that the human CrebA orthologues, Creb3L1 and Creb3L2, have the ability to upregulate the secretory pathway in non-secretory cell types. Goals: The goals of the microarray experiments were to identify additional targets of the CrebA transcription factor to learn the range of genes regulated by this transcription factor during embryogenesis. Previous work had indicated that CrebA upregulates the protein machinery of the early secretory pathway. Our new data now shows that in addition to the protein machinery, CrebA also upregulates genes encoding the protein cargo that is secreted from specialized secretory organs.

2010-10-18 | GSE23346 | GEO

Golgi Outpost Synthesis Impaired by Toxic Polyglutamine Proteins Contributes to Dendritic Pathology in Neurons

Project description:Dendrite aberration is a common feature of neurodegenerative diseases caused by protein toxicity, but the underlying mechanisms remain largely elusive. Here, we show that nuclear polyglutamine (polyQ) toxicity resulted in defective terminal dendrite elongation accompanied with a loss of Golgi outposts (GOPs) and decreased supply of plasma membrane (PM) in Drosophila Class IV da (C4da) neurons. mRNA sequencing revealed that down-regulated genes by polyQ proteins included many secretory pathway-related genes, including COPII genes regulating GOP synthesis. Transcription factor enrichment analysis identified CREB3L1/CrebA, which regulates COPII gene expression. CrebA overexpression in C4da neurons restored the dysregulation of COPII genes, GOP synthesis, and PM supply. The ChIP-PCR assay revealed that CrebA expression was regulated by CBP, which was sequestered by polyQ proteins. Furthermore, co-overexpression of CrebA and Rac1 synergistically restored the polyQ-induced dendrite pathology. Collectively, our results suggest that GOPs impaired by polyQ proteins contribute to dendrite pathology through the CBP-CrebA-COPII pathway.

2017-06-27 | GSE65538 | GEO

Homo sapiens

Project description:Active Creb3L1 can upregulate secretory pathway genes in HeLa cells

| PRJNA133299 | ENA

Genome-wide binding of CrebA in the Drosophila salivary gland

Project description:Salivary gland-specific binding assays reveal that CrebA, a bZIP transcription factor, directly binds the vast majority of genes encoding the secretory machinery, including proteins of the signal recognition particle and receptor, proteins involved in co-translational import of cargo into the ER, proteins involved in vesicular transport between the ER and Golgi, as well as the structural proteins and enzymes of these organelles. CrebA does not bind salivary gland-specific cargo genes. Instead, it binds and boosts expression of Sage, which encodes a bHLH transcription factor that upregulates cargo expression. CrebA also directly binds and upregulates Xbp1, which encodes a key factor in the unfolded protein response, and Tudor-SN, which encodes a protein that in other systems increases secretory cargo mRNA levels.

2021-01-01 | GSE141778 | GEO

Gene module reconstruction elucidates cellular differentiation processes and the regulatory logic of specialized secretion

Project description:During differentiation, cells become structurally and functionally specialized, but comprehensive views of the underlying remodeling processes are elusive. Here, we leverage scRNA-seq developmental trajectories to reconstruct differentiation, using two secretory tissues as a model system – the zebrafish notochord and hatching gland. First, we present an approach (MIMIR) to integrate expression and functional similarities for gene module identification, revealing dozens of gene modules representing known and newly associated differentiation processes and their temporal ordering. Second, we focused on the unfolded protein response (UPR) transducer module to study how general versus cell-type specific secretory functions are regulated. By profiling loss- and gain-of-function embryos, we found that the UPR transcription factors creb3l1, creb3l2, and xbp1 are master regulators of a general secretion program. creb3l1/creb3l2 additionally activate an extracellular matrix secretion program, while xbp1 partners with bhlha15 to activate a gland-specific secretion program. Our study offers an integrated approach for functional gene module identification and illustrates how transcription factors confer general and specialized cellular functions.

2024-01-29 | GSE252032 | GEO

Combination treatment with metformin and tacrolimus improves systemic immune cellular homeostasis by modulating Treg and Th17 imbalance

Project description:Recycling and supply of plasma membrane (PM), referred to as PM turnover, are essential for maintaining integrity of neurons undergoing continuous dynamic morphological changes. Yet, the link of PM turnover to neuronal pathophysiology remains largely elusive. Here we showed that a subset of toxic polyglutamine proteins markedly compromised local targeting-recycling of PM components, reflecting a unique feature of early neuropathies. Such disruption of PM turnover in dendrites was ascribed primarily to alterations in dendritic endosomes and Golgi outposts accounting for local PM recycling and supply, respectively. Genome-wide mRNA-sequencing analysis identified CREB3L1/CrebA-COPII pathway to be responsible for the disruption of PM turnover. Indeed, CrebA overexpression reversed PM turnover impairment caused by these toxic proteins through restoring COPII pathway. Thus we demonstrate how PM turnover is linked to aberration of neuronal integrity in pathological conditions as well as its near-complete restoration through genetic engineering of CREB3L1/CrebA-COPII pathway.

2020-11-11 | GSE161187 | GEO

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