"Spot 14" Protein: A Metabolic Integrator in Normal and Neoplastic Cells

Abstract

"Spot 14" (S14) was originally identified as a mRNA from rat liver that responded rapidly to thyroid hormone, and has now been shown to play a key role in the tissue-specific regulation of lipid metabolism. In addition to its responsiveness to thyroid hormone, S14 gene transcription is controlled by dietary substrates, such as glucose and polyunsaturated fatty acids, and by fuel-related hormones including insulin and glucagon. The S14 protein forms homodimers via a carboxyl-terminal "zipper" domain. The protein is located primarily in the cell nucleus, and its expression in liver is limited to the perivenous portion of the hepatic lobule, the site of fatty acid synthesis. S14 protein is critical for the induction of key enzymes involved in the switching of hepatic metabolism from the fasted to the fed state. S14 antisense oligonucleotides inhibit both the intracellular production of lipids and their export as very low-density lipoprotein (VLDL) particles. S14 acts at the level of transcription to regulate expression of genes encoding key metabolic enzymes, including those required for long-chain fatty acid synthesis. The human S14 gene is located at 11q13.5, a region that is amplified in a subset of aggressive breast cancers. S14 mRNA is expressed in most breast cancer-derived cell lines, and the protein is found in the nuclei of two thirds of human breast cancer specimens, but not in normal nonlactating mammary glands. S14 expression in breast tumors is highly concordant with overabundance of a key lipogenic enzyme. This indicates the association of S14 with enhanced tumor lipogenesis, an established marker of poor prognosis. In addition to the utility of S14 as a model system for elucidation of the mechanism of thyroid hormone action, studies of its regulation and function have provided insights into tissue-specific metabolic control by hormones and dietary substrates in both normal and neoplastic tissues.

Recent advances in the regulation of milk fat synthesis

“…We identified thyroid hormone responsive spot 14 (S14) as a trans-10, cis-12 CLA responsive gene in the microarray analysis of bovine mammary cultures . The S14 gene encodes a nuclear protein that is closely associated with the regulation of lipid synthesis in lipogenic tissues, including the bovine mammary gland (Cunningham et al, 1998;. Furthermore, we established that the expression of S14 in the bovine mammary gland is down-regulated in both CLA-and diet-induced MFD .…”

“…Furthermore, we established that the expression of S14 in the bovine mammary gland is down-regulated in both CLA-and diet-induced MFD . Although its exact biochemical function is not known, S14 is found in the nucleus and is a putative transcriptional coactivator (Cunningham et al, 1998;Chou et al, 2007 and that is highly responsive to pro-lipogenic signals including SREBP1 activation (Martel et al, 2006). The expression of S14 is positively associated with conditions of excessive lipid synthesis, including human obesity, chicken lines selected for increased growth and adiposity, muscle of cattle selected for marbling and high lipogenic cancers (summarized in .…”

“…Studies of the function of S14 have provided interesting insight, and also many inconsistencies (see review by LaFave et al, 2006). Knock-down of S14 in hepatocyte culture resulted in decreased expression of lipogenic enzymes (reviewed by Cunningham et al, 1998), but the S14 knockout mouse had increased hepatic lipogenesis (Zhu et al, 2001). Of special interest in considering possible relevance to MFD, S14 knock-out mice had a 62% reduction in mammary lipogenesis and a 26% reduction in milk clot triglyceride concentration, which was predominantly due to decreased de novo fatty acid synthesis; however, activities of mammary lipogenic enzymes were unaltered (Zhu et al, 2005).…”

Nutrient-gene interactions: a single nutrient and hundreds of target genes

“…S14 is only expressed in tissues active in lipogenesis and its transcript levels are not only dependent on T3, but also controlled by other stimuli such as carbohydrates (via carbohydrate-responsive elements; ChoREs) that in turn modulate fatty acid synthesis in rodent liver (Koo and Towle, 2000). S14 is mainly found in the perivenous portion of the hepatic lobule as the main site of fatty acid synthesis and is critical for the induction of key enzymes involved in the switching of hepatic metabolism from the fasted to the fed state (Cunningham et al, 1998). Does the increased S14 mRNA level in rat liver as observed here in zinc deficiency lead to concomitant changes in hepatic fat metabolism?…”

Non-classic thyroid hormone signalling involved in hepatic lipid metabolism

“…Besides the direct effect in the transcription of these enzymes, thyroid hormones promote a rapid and important increase in Spot14 (S14 (THRSP)) expression, a protein which is able to interact physically and functionally with the thyroid hormone receptor (TR) to regulate malic enzyme gene expression (Chou et al 2007). The elevated S14 expression is important to increase lipogenic enzyme expressions induced by T 3 (Cunningham et al 1998). In this way, hyperthyroid patients present approximately a threefold increase in hepatic lipogenesis when compared with euthyroid subjects (Cachefo et al 2001).…”