Hyperphosphorylation regulates the activity of SREBP1 during mitosis

Bengoechea-Alonso, Maria T.; Punga, Tanel; Ericsson, Johan

doi:10.1073/pnas.0501494102

Cited by 58 publications

(67 citation statements)

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“…SIRT1 acts as a sensor and a regulator in the metabolism of cancer (28). SREBP1 is the pivotal transcription factor in lipogenesis (29), and Bengoechea-Alonso et al speculated that SREBP1 may provide a link between lipid synthesis, and cell growth and proliferation (30). Based on these findings, some researchers have found that SREBP1 plays a role as an oncogene in human cancer (12)(13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

Zheng

Qiu

et al. 2014

Oncology Reports

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Abstract. Silent information regulator 1 (SIRT1) is involved in a number of cellular regulatory mechanisms affecting cellular life span, stress resistance, apoptosis and cellular metabolism. Recent studies have revealed that SIRT1 plays a dual role as a tumor suppressor and a tumor promoter in multiple stages of carcinogenesis. Increased lipogenesis has been found in cancer cells, sterol regulatory element binding protein 1 (SREBP1) are nuclear lipogenic transcription factors, which mainly regulate lipogenic processes by activating genes involved in fatty acid and triglyceride biosynthesis. In the present study, we detected expression of SIRT1 in endometrial cancer (EC) and illustrated the relationship between SIRT1 and SREBP1, which indicated that SIRT1 could stimulate endometrial tumor growth through the lipogenic pathway. Gene expression levels of SIRT1 were assayed using quantitative real-time PCR and protein expression levels were detected by western blotting. RNA interference was conducted in order to explore the subsequent effect on tumor cells and on the expression of SREBP1. Expression levels of SIRT1 in EC were found to be significantly higher than in normal endometrium. Knockdown of SIRT1 could downregulate expression of SREBP1 and suppress cell proliferation. These results demonstrated that SIRT1 may play a role as a tumor promoter in EC and can promote endometrial tumor growth by promoting lipogenesis. Our findings suggest that targeting SIRT1 may provide a theoretical basis for the management of EC. IntroductionEndometrial cancer (EC) is the most common malignancy of the female reproductive tract and its incidence is on the increase (1). Approximately 40% of all cases can be attributed to obesity (2). Aberration in lipid metabolism contributes to different aspects of tumorigenesis (3); our research team focused on this domain of EC in recent years.NAD-dependent class III histone deacetylase silent information regulator 1 (SIRT1), that shares the highest degree of homology with the yeast protein SIR2, can deacetylate both histones and non-histone proteins (4). Its deacetylation activity enables it to interact with a variety of important transcription factors and transcriptional co-regulatory factors, to regulate gene transcription, chromosome stability and activity of target proteins, which are involved in tumor metabolism and development (5,6). The current results demonstrated that SIRT1 plays a dual role as a tumor promoter as well as a tumor suppressor (7). Its involvement in tumorigenesis may be due to its diverse distribution in different tissues and different upstream and downstream regulatory factors that regulate its function (8).Sterol regulatory element binding protein 1 (SREBP1) belongs to the family of the basic helix-loop-helix leucine zipper family of DNA binding transcription factors, which can regulate most enzymes involved in fatty acid biosynthesis, such as acetyl-CoA carboxylase, fatty acid synthase, Elovl-6 and stearoyl-CoA desaturase (9). Lipogenesis is increased in cancer cells...

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Section: Discussionmentioning

confidence: 99%

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

Zheng

Qiu

et al. 2014

Oncology Reports

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“…S3 and Ref. 9), no enhanced interaction between the ⌬C protein and GSK-3␤ was observed in response to DNA binding (Fig. 3E, fourth lane).…”

Section: Srebp1 Is Hyperphosphorylated Inmentioning

confidence: 99%

“…Plasmids and DNA Transfections-The mammalian expression vectors for FLAG-tagged SREBP1a and the bacterial expression vectors for His 6 -SREBP1a and His 6 -SREBP2 have been described (9). The HMG-CoA synthase (SYNSRE-luc) and low density lipoprotein receptor (LDLr) promoter-reporter constructs and the expression vectors for Fbw7␣ and cullin1 have been described previously (8, 26 -28).…”

Section: Methodsmentioning

confidence: 99%

“…ChIP Assays-The ChIP assays were performed with the indicated antibodies as described previously (9). The PCR amplifications were performed in the presence of 1 Ci of [ 32 P]dCTP and analyzed in 6% polyacrylamide gels.…”

Section: Methodsmentioning

confidence: 99%

“…These transcriptionally active fragments of the SREBPs are translocated to the nucleus and bind to the promoters of SREBP target genes (6). It has been demonstrated that the mature forms of SREBPs are modified by phosphorylation (7)(8)(9), acetylation (10), sumoylation (11), and ubiquitination (8,12), and it has been shown that these modifications regulate their stability and/or transcriptional activity.…”

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Phosphorylation and Ubiquitination of the Transcription Factor Sterol Regulatory Element-binding Protein-1 in Response to DNA Binding

Punga¹,

Bengoechea-Alonso²,

Ericsson

2006

Journal of Biological Chemistry

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109

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Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors control cholesterol and lipid metabolism and play critical roles during adipocyte differentiation. The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr 426 and Ser 430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3␤-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding. DNA binding enhances the direct interaction between the C-terminal domain of SREBP1 and GSK-3␤. Accordingly, we demonstrate that GSK-3␤ is recruited to the promoters of SREBP target genes in vivo. As a result of the phosphorylation of Thr 426 and Ser 430 , the ubiquitin ligase Fbw7 is recruited to SREBP molecules associated with target promoters. Using a reconstituted ubiquitination system, we demonstrate that Fbw7-mediated ubiquitination of SREBP1 is dependent on its DNA binding activity. Thus, DNA binding could provide a mechanistic link between the phosphorylation, ubiquitination, and degradation of active transcription factors.Members of the sterol regulatory element-binding protein (SREBP) 3 family of transcription factors control cholesterol and lipid metabolism and play critical roles during adipocyte differentiation and insulin signaling (1, 2). The SREBP family of transcription factors consists of three different SREBP proteins; SREBP1a, SREBP1c, and SREBP2. The SREBPs are synthesized as large precursor proteins that are inserted into the nuclear and endoplasmic reticulum membranes and are transcriptionally inactive (3). In sterol-depleted cells, SREBPs are processed sequentially by two membrane-associated proteases that release the mature form of the proteins (4, 5). These transcriptionally active fragments of the SREBPs are translocated to the nucleus and bind to the promoters of SREBP target genes (6). It has been demonstrated that the mature forms of SREBPs are modified by phosphorylation (7-9), acetylation (10), sumoylation (11), and ubiquitination (8, 12), and it has been shown that these modifications regulate their stability and/or transcriptional activity.Many transcription factors, particularly those involved in the control of cell growth, are unstable proteins targeted for degradation by the ubiquitin-proteasome system (13). Numerous observations have pointed to the existence of a close connection between the ubiquitin-proteasome system and transcriptional activation (14,15). It has been demonstrated that the sequences that specify proteolysis of some activators overlap with their transcriptional activation domains and that components of the proteasome can be recruited to promoters through interactions with transcriptional regulators (16 -21). It has also been demonstrated that the activity of certain transcription factors can be enhanced by ubiquitination or through interactions with specific ubiquitin ligases (22-25). However, the mechanistic link between the transcriptional activity of...

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Nutritional genomics for the characterization of the effect of bioactive molecules in lipid metabolism and related pathways

Daimiel¹,

Vargas²,

Molina

2012

Electrophoresis

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Cardiovascular disease and cancer are the main causes of morbidity and mortality worldwide. Thus, investigators have focused their efforts on gaining insight into understanding the mechanisms involved in the development and evolution of these diseases. In the past decade, and with the contribution of the ‐omics technologies, strong evidence has supported an essential role of gene–nutrient interactions in these processes, pointing at natural bioactive molecules as promising complementary agents that are useful in preventing or mitigating these diseases. In addition, alterations in lipid metabolism have recently gained strong interest since they have been described as a common event required for the progression of both diseases. In the present review, we give an overview of lipid metabolism, mainly focusing on lipoprotein metabolism and the mechanisms controlling lipid homeostasis. In addition, we review the modulation of lipid metabolism by bioactive molecules, highlighting their potential use as therapeutic agents in preventing, and treating chronic diseases such as cardiovascular disease and cancer. Finally, we report the usefulness of the ‐omics technologies in nutritional research, focusing on recent findings, within nutritional genomics, in the interaction of bioactive components from foods with several genes that are involved in the development and progression of these diseases.

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Hyperphosphorylation regulates the activity of SREBP1 during mitosis

Cited by 58 publications

References 34 publications

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

SIRT1 promotes endometrial tumor growth by targeting SREBP1 and lipogenesis

Phosphorylation and Ubiquitination of the Transcription Factor Sterol Regulatory Element-binding Protein-1 in Response to DNA Binding

Nutritional genomics for the characterization of the effect of bioactive molecules in lipid metabolism and related pathways

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