DEFINITION
Sterol regulatory element binding protein are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.
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CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Model (Width 700 px)
SYNTHESIS AND TURNOVER
mRNA synthesis
protein synthesis
post-translational modifications
SRBP1 (Glu/Gln = 0.78 old and expressed in hypoxia)
SRBP2 (Glu/Gln = 0.62 old and expressed in hypoxia)
SCAP (Glu/Gln = 1.42 recent and expressed in rather high O2)
S1P = MBTP1 (Glu/Gln = 1.14 old and expressed in mild hypoxia)
S2P = MBTP2 (Glu/Gln = 0.68 old and expressed in hypoxia)
apparently the original system started with:
- SRBP1 and SRBP2 activated by MBTP2
- MBPT2
- at higher pO2 SCAP inhibits biosynthetic pathways
degradation
CELLULAR FUNCTIONS
cellular localization,
Mol Cell Endocrinol. 2009 May 6;303(1-2):1-6. Epub 2009 Jan 22.
New functions of cholesterol binding proteins. 2009
Liu JP.
Department of Immunology, Monash University Central Clinical School, Prahran, Victoria, Australia. jun-ping.liu@med.monash.edu.au
Abstract
Cholesterol is an essential component of eukaryotic cell membranes with an important role in signal transduction. Although cholesterol can operate to auto-regulate its own disposal via gene transcriptional mechanisms, glucose also binds to the same cholesterol-binding transcription factors to regulate gene expression. Different sterol binding proteins bind different lipids to regulate both lipid homeostasis and antigen presentation. This mini-review examines the recently reported new functions of cholesterol binding proteins in cholesterol homeostasis, function and trafficking, and explores the molecular mechanisms whereby sterol sensors respond to glucose and other ligands to regulate diverse cellular functions in metabolism. Several new models are proposed from studies on a range of sterol binding proteins including Insig, SCAP, LXR, HMG-CoAR, NPC1 and NPC2.
biological function
One more figure
Regulated expression of the SREBPs is complex in that the effects of sterols are different on the SREBP-1 gene versus the SREBP-2 gene.
Cellular cholesterol trafficking and compartmentalization 2008
- Enzymes
- Cell signaling and Ligand transport
- Structural proteins
REGULATION
DIAGNOSTIC USE
SREBP
In the case of SREBP there is no extracellular peptide and therefore it only act as transcription factor
SCAP2 and cell proliferation
Spatial and temporal expression of RA70/Scap2 in the developing neural tube. 2014
- Ra70/scap2 was expressed in the ependymal layer and ventricular zone in the neural tube, where neuroepithelial cells and neuroblasts with proliferation capacity are localized, respectively. Thus, RA70/Scap2 may be necessary for RA-induced neuronal differentiation from the posterior neuroectoderm.
INS1 INS2 and cell proliferation
Epithelial SCAP/INSIG/SREBP signaling regulates multiple biological processes during perinatal lung maturation. 2014
- Through comprehensive data analysis and integration, time dependent effects of epithelial SCAP/INSIG/SREBP deletion and defined SCAP/INSIG/SREBP-associated genes, bioprocesses and downstream pathways were identified
Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. 2010
- Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and increase metabolism. Progesterone receptor membrane component 1 (Pgrmc1) is related to cytochrome b5, binds to heme, and is associated with DNA damage resistance and apoptotic suppression. Pgrmc1 is induced by carcinogens, including dioxin, and is up-regulated in multiple types of cancer. In the present study, we found that Pgrmc1 increased in vivo tumor growth, anchorage-independent growth, and migration. Pgrmc1 also promoted proliferation in the absence of serum in A549 non-small cell lung cancer cells but enhanced proliferation regardless of serum concentration in MDA-MB-468 breast cancer cells. Pgrmc1 promotes cholesterol synthesis and binds to Insig (insulin-induced gene), Scap (sterol regulatory element binding protein cleavage activating protein), and P450 proteins, but Pgrmc1 did not affect cholesterol synthesis in lung cancer cells. Pgrmc1 is also associated with progesterone signaling and plasminogen activator inhibitor (PAI1) RNA binding protein, but neither progesterone activity nor PAI1 transcript levels were altered in Pgrmc1-knockdown lung cancer cells. Pgrmc1 homologues bind to aryl ligands identified in an in silico screen, and we have found that a Pgrmc1 ligand induced cell death in a Pgrmc1-specific manner in multiple breast and lung tumor cell lines. Our data support a role for Pgrmc1 in promoting cancer-associated phenotypes and provide a therapeutic approach for targeting Pgrmc1 with a small molecule in lung and breast cancer.
caption and paper link
figures SCAP INSIG:
