Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCFFbw7

Sundqvist, Anders; Bengoechea-Alonso, Maria T.; Ye, Xin; Lukiyanchuk, Vasyl; Jin, Jianping; Harper, J. Wade; Ericsson, Johan

doi:10.1016/j.cmet.2005.04.010

Cited by 387 publications

(409 citation statements)

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“…Early observations indicated that SREBP1a is phosphorylated in vivo (14). Subsequently, it has been suggested that both SREBP1 and SREBP2 are phosphorylated by various protein kinases, both in vivo and in vitro (15)(16)(17). We were interested in mapping the major phosphorylated residues in SREBP1, especially those found in the Ser͞Thr͞Gly-rich C terminus of the mature protein (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the C terminus of mature SREBP1 contains two PEST motifs, sequences that are usually found in unstable proteins. Phosphorylation of Ser and Thr residues within PEST motifs have been shown to regulate the degradation of a number of proteins (29), including SREBPs (15). The C terminus of mature SREBP1 contains a total of 19 Ser and Thr residues, and it will be important to determine which of these are phosphorylated and how these modifications affects the stability of the protein.…”

Section: Discussionmentioning

confidence: 99%

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Hyperphosphorylation regulates the activity of SREBP1 during mitosis

Bengoechea-Alonso

Punga

Ericsson

2005

Proc. Natl. Acad. Sci. U.S.A.

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The sterol regulatory element-binding protein (SREBP) family of transcription factors controls the biosynthesis of cholesterol and other lipids, and lipid synthesis is critical for cell growth and proliferation. We were, therefore, interested in the expression and activity of SREBPs during the cell cycle. We found that the expression of a number of SREBP-responsive promoter-reporter genes were induced in a SREBP-dependent manner in cells arrested in G 2͞M. In addition, the mature forms of SREBP1a and SREBP1c were hyperphosphorylated in mitotic cells, giving rise to a phosphoepitope recognized by the mitotic protein monoclonal-2 (MPM-2) antibody. In contrast, SREBP2 was not hyperphosphorylated in mitotic cells and was not recognized by the MPM-2 antibody. The MPM-2 epitope was mapped to the C terminus of mature SREBP1, and the mitosis-specific hyperphosphorylation of SREBP1 depended on this domain of the protein. The transcriptional and DNA-binding activity of SREBP1 was enhanced in cells arrested in G 2͞M, and these effects depended on the C-terminal domain of the protein. In part, these effects could be explained by our observation that mature SREBP1 was stabilized in G 2͞M. In agreement with these observations, we found that the synthesis of cholesterol was increased in G 2͞M-arrested cells. Thus, our results demonstrate that the activity of mature SREBP1 is regulated by phosphorylation during the cell cycle, suggesting that SREBP1 may provide a link between lipid synthesis, proliferation, and cell growth.cell cycle ͉ cholesterol ͉ phosphorylation ͉ proliferation M embers of the sterol regulatory element-binding protein (SREBP) family of transcription factors control cholesterol and lipid metabolism and play critical roles in insulin signaling and during adipocyte differentiation (1). Two genes, srebf1 and srebf2, encode three different SREBPs (SREBP1a, SREBP1c, and SREBP2) (2). SREBPs are synthesized as large precursor proteins that are inserted into the nuclear and endoplasmic reticulum (ER) membranes and are transcriptionally inactive. In sterol-depleted cells, SREBP cleavage-activating protein (SCAP) escorts SREBP to the Golgi apparatus where SREBP is processed sequentially by two membrane-associated proteases, resulting in the release of the mature form of the protein (3, 4). This transcriptionally active fragment of SREBP is translocated to the nucleus and binds to the promoters of SREBP target genes. Most of these genes are involved in the control of lipid biosynthesis and metabolism (5). In sterolloaded cells, the SCAP͞SREBP complex is trapped in the ER as a result of sterol-induced binding of SCAP to Insigs, which are resident proteins of the ER membrane (6, 7).It is well established that the synthesis of membrane lipids is critical for cell growth and proliferation (8, 9). Here, we report that the expression of a number of SREBP-responsive promoterreporter genes are induced in a SREBP-dependent manner in cells arrested in G 2 ͞M. In addition, the mature forms of SREBP1a and SREBP1c are hyperphosphory...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hyperphosphorylation regulates the activity of SREBP1 during mitosis

Bengoechea-Alonso

Punga

Ericsson

2005

Proc. Natl. Acad. Sci. U.S.A.

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“…It is also possible that insulin may be involved in the transcriptional activity of SREBP1c through other regulatory mechanisms. Recent studies indicate that glycogen synthase kinase-3 (GSK-3) could phosphorylate SREBP1c, resulting in its ubiquitination and proteasomal degradation [21]. Insulin is known to inhibit GSK-3 activity via PKB dependent phosphorylation [5].…”

Section: Discussionmentioning

confidence: 99%

Fatty acid synthase gene regulation in primary hypothalamic neurons

Kim

Kleman

Ronnett

2007

Neuroscience Letters

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Understanding the mechanisms that regulate feeding is critical to the development of therapeutic interventions for obesity. Many studies indicate that enzymes within fatty acid metabolic pathways may serve as targets for pharmacological tools to treat this epidemic. We, and others have previously demonstrated that C75, a fatty acid synthase (FAS) inhibitor, induced significant anorexia and weight loss by both central and peripheral mechanisms. Because the hypothalamus is important in the regulation of homeostatic processes for feeding control, we have identified pathways that alter the gene expression of FAS in primary hypothalamic neuronal cultures. Insulin, glucose and AICAR (an activator of AMP-activated protein kinase) affected changes in hypothalamic FAS mRNA, which may be regulated via the SREBP1c dependent or independent pathway.

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“…Sequences recognized by Fbxw7 in c-Myc, c-Jun and SREBP1a or -1c are phosphorylated by glycogen synthase kinase-3b (GSK-3b), resulting in the ubiquitylation and degradation of these proteins (Welcker et al, 2004;Yada et al, 2004;Sundqvist et al, 2005;Wei et al, 2005). NICD1 is also phosphorylated by GSK-3b.…”

Section: Discussionmentioning

confidence: 99%