title: The phosphorylation-dependent regulation of nuclear SREBP1 during mitosis links lipid metabolism and cell growth.
abstract: The SREBP transcription factors are major regulators of lipid metabolism. Disturbances in lipid metabolism are at the core of several health issues facing modern society, including cardiovascular disease, obesity and diabetes. In addition, the role of lipid metabolism in cancer cell growth is receiving increased attention. Transcriptionally active SREBP molecules are unstable and rapidly degraded in a phosphorylation-dependent manner by Fbw7, a ubiquitin ligase that targets several cell cycle regulatory proteins for degradation. We have previously demonstrated that active SREBP1 is stabilized during mitosis. We have now delineated the mechanisms involved in the stabilization of SREBP1 in mitotic cells. This process is initiated by the phosphorylation of a specific serine residue in nuclear SREBP1 by the mitotic kinase Cdk1. The phosphorylation of this residue creates a docking site for a separate mitotic kinase, Plk1. Plk1 interacts with nuclear SREBP1 in mitotic cells and phosphorylates a number of residues in the C-terminal domain of the protein, including a threonine residue in close proximity of the Fbw7 docking site in SREBP1. The phosphorylation of these residues by Plk1 blocks the interaction between SREBP1 and Fbw7 and attenuates the Fbw7-dependent degradation of nuclear SREBP1 during cell division. Inactivation of SREBP1 results in a mitotic defect, suggesting that SREBP1 could regulate cell division. We propose that the mitotic phosphorylation and stabilization of nuclear SREBP1 during cell division provides a link between lipid metabolism and cell proliferation. Thus, the current study provides additional support for the emerging hypothesis that SREBP-dependent lipid metabolism may be important for cell growth.
authors: a University College Dublin, School of Medicine and Medical Science, UCD Conway Institute , Dublin , Ireland.
authors: Maria Teresa
authors: MT
authors: Bengoechea-Alonso
authors: a University College Dublin, School of Medicine and Medical Science, UCD Conway Institute , Dublin , Ireland.
authors: Johan
authors: J
authors: Ericsson
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism; D008938:Mitosis; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1; C513273:FBXW7 protein, human
keywords: Fbw7; Plk1; SREBP; cancer; cholesterol; lipids; mitosis