Induction of Serum Amyloid A (SAA) Gene by SAA-activating Sequence-binding Factor (SAF) in Monocyte/Macrophage Cells

Abstract

Serum amyloid A (SAA) is a plasma protein that is associated with many inflammatory diseases including amyloidosis, arthritis, and atherosclerosis. SAA level is significantly increased during inflammatory condition, and such abnormal expression of this protein is linked to the pathogenesis of the above-mentioned diseases. A promoter element, designated as SAA-activating sequence (SAS), located between ؊280 and ؊226 has been implicated in the induction mechanism and a nuclear factor, SAS-binding factor (SAF), has been shown to bind to this region. In this report, using a cloned SAF gene in transient transfection assay, we provide evidence that SAF potentiates SAA gene expression through SAS element. Furthermore, we show that during lipopolysaccharide-mediated induction of SAF, heteromeric complex with transcription factor Sp1 is formed. Transfection assays using both transcription factor genes have demonstrated that SAF-Sp1 heteromer is a highly potent transactivator of SAA expression.

Isolation and Functional Characterization of cDNA of Serum Amyloid A-Activating Factor That Binds to the Serum Amyloid A Promoter

“…Multiple proteins may interact via these proline-rich regions to form an optimum preinitiation complex for transcription. We recently reported that SAF can interact with Sp1 to form an SAF-Sp1 heteromeric complex which has a higher level of transactivation potential than SAF or Sp1 alone (39,40). It will be interesting to know whether the proline-rich domain of SAF is involved in such an interaction.…”

A SAF Binding Site in the Promoter Region of Human γ-Fibrinogen Gene Functions as an IL-6 Response Element

“…SAF-1 protein is inflammation responsive and is activated in several cell types, including the liver. LPS, IL-6, and minimally modified low density lipoprotein particles are a few among the known activating agents of SAF-1 (17)(18)(19)(20)(21). However, because SAF-1 is not expressed exclusively in the liver, liver-specific induction of the ␥-fibrinogen gene may not be mediated solely by this factor and may require some assistance.…”

“…One member of this family, SAF-1, is homologous to human MAZ (28) or mouse Pur-1 (29). The broad array of other target genes that this family of proteins regulate are SAA (17)(18)(19)(20)(21), c-myc (28), insulin (29), serotonin 1A receptor (30), and the CD4 receptor (31). SAF-1 protein is inflammation responsive and is activated in several cell types, including the liver.…”

Serum Amyloid A-Luciferase Transgenic Mice: Response to Sepsis, Acute Arthritis, and Contact Hypersensitivity and the Effects of Proteasome Inhibition

“…Both genes are similarly regulated by the proinflammatory cytokines IL-1, IL-6, and TNF-␣ in hepatic cells (6). The regulation of SAA genes involves a number of transcription factors, such as NF-B, C/EBPs, AP-2, Yin Yang 1, sequence-binding factor, and specificity protein 1 (4,(7)(8)(9)(10)(11). Under acute inflammatory conditions triggered by LPS, both SAA1 and SAA2 are induced to a similar extent, causing up to a 1000-fold increase in the serum A-SAA concentration (3).…”