Suppression of vascular endothelial growth factor expression in breast cancer cells by microRNA-125b-mediated attenuation of serum amyloid A activating factor-1 level.

Increased level of an inflammation-responsive transcription factor called serum amyloid A-activating factor (SAF-1) has been linked to the pathogenesis in human breast cancer. SAF-1 is found to promote vascular endothelial growth factor (VEGF) expression in breast carcinoma cells and boost angiogenesis. In an effort to develop a cellular mechanism to control VEGF expression, we sought to limit SAF-1 activity in breast cancer cells.

Metformin induces degradation of mTOR protein in breast cancer cells.

Activation of mTOR is implicated in the development and progression of breast cancer. mTOR inhibition exhibited promising antitumor effects in breast cancer; however, its effect is compromised by several feedback mechanisms. One of such mechanisms is the upregulation of mTOR pathway in breast cancer cells.

Insulin signaling network in cancer.

The primary function of insulin is viewed as a hormone that controls blood glucose level. However, there is growing evidence that aberrant insulin level and insulin-mediated signaling can lead to cancer development and progression. The insulin-cancer relationship has stemmed from various observational and epidemiological studies, which linked higher incidence of cancer with central obesity, type II diabetes and other conditions associated with increased levels of circulating insulin, insulin resistance and hyperinsulinemic states.

Induction of Ras by SAF-1/MAZ through a feed-forward loop promotes angiogenesis in breast cancer.

In the majority of breast cancers, overexpression and hyperactivation of Ras in the tumor microenvironment play significant role in promoting cancer cell growth, angiogenesis, and metastasis. We have previously shown that vascular endothelial growth factor (VEGF) expression in triple negative breast cancer cells is regulated, at least in part, by SAF-1 (serum amyloid A activating factor 1) transcription factor. In this study we show that transformation of normal MCF-10A breast epithelial cells by constitutively active, oncogenic Ras, induces the DNA-binding activity and transcription function of SAF-1.

Loss of epigenetic Kruppel-like factor 4 histone deacetylase (KLF-4-HDAC)-mediated transcriptional suppression is crucial in increasing vascular endothelial growth factor (VEGF) expression in breast cancer.

Vascular endothelial growth factor (VEGF) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions, including cancer, inflammation, and ischemic disorders. We have recently shown that the inflammatory transcription factor SAF-1 is, at least in part, responsible for the marked increase of VEGF levels in breast cancer. Here, we show that SAF-1-mediated induction of VEGF is repressed by KLF-4 transcription factor.

The effect of fasting on indicators of muscle damage.

Many studies have tested the consumption of foods and supplements to reduce exercise-induced muscle damage, but fasting itself is also worthy of investigation due to reports of beneficial effects of caloric restriction and/or intermittent fasting on inflammation and oxidative stress. This preliminary investigation compared indicators of exercise-induced muscle damage between upper-body untrained participants (N=29, 22yrs old (SD=3.34), 12 women) who completed 8h water-only fasts or ate a controlled diet in the 8h prior to five consecutive laboratory sessions.

Epigenetic regulation by Z-DNA silencer function controls cancer-associated ADAM-12 expression in breast cancer: cross-talk between MeCP2 and NF1 transcription factor family.

A disintegrin and metalloprotease domain-containing protein 12 (ADAM-12) is upregulated in many human cancers and promotes cancer metastasis. Increased urinary level of ADAM-12 in breast and bladder cancers correlates with disease progression. However, the mechanism of its induction in cancer remains less understood.

Control of VEGF expression in triple-negative breast carcinoma cells by suppression of SAF-1 transcription factor activity.

Angiogenesis plays a significant role in cancer by providing increased blood supply to the affected tissues and thus bringing in growth factors, cytokines, and various nutrients for tumor growth. VEGF is the most prominent angiogenic agent that is markedly induced in cancer. Induction of VEGF has been widely studied but as cancer cells are quite adept at acquiring new alternative processes to circumvent surrounding environmental pressures, our understanding of the molecular mechanisms regulating VEGF expression in cancer, especially in triple-negative breast cancer cells, remains incomplete.

Z-DNA-forming silencer in the first exon regulates human ADAM-12 gene expression.

Upregulation of ADAM-12, a novel member of the multifunctional ADAM family of proteins is linked to cancer, arthritis and cardiac hypertrophy. Basal expression of ADAM-12 is very low in adult tissues but rises markedly in response to certain physiological cues, such as during pregnancy in the placenta, during development in neonatal skeletal muscle and bone and in regenerating muscle. Studies on ADAM-12 regulation have identified a highly conserved negative regulatory element (NRE) at the 5'-UTR of human ADAM-12 gene, which acts as a transcriptional repressor.

Role of p21 and cyclin E in normal and secalonic acid D-inhibited proliferation of human embryonic palatal mesenchymal cells.

Secalonic acid D (SAD), a cleft palate-inducing teratogen, has been shown to inhibit proliferation/cell cycle progression in association with alteration in the levels of cell cycle regulators, p21 and cyclin E. These studies were conducted to test the hypotheses that p21 and cyclin E play an important functional role in normal human embryonic palatal mesenchymal (HEPM) cell cycle and that their up- and down-regulation, respectively, by SAD is functionally significant to its cell cycle block. Using small interfering RNA (siRNA) to silence p21 gene and transient transfection to overexpress cyclin E in control & SAD-treated HEPM cells, cell proliferation was assessed using a combination of cell numbers, thymidine uptake, CDK2 activity and Ki-67 expression.

Transforming growth factor-beta1-mediated activation of NF-kappaB contributes to enhanced ADAM-12 expression in mammary carcinoma cells.

A disintegrin and metalloproteinase-12 (ADAM-12), a member of multifunctional family of proteins, is upregulated in many cancers, including breast, lung, liver, prostate, gastric, and bladder. The multidomain structure, composed of a prodomain, a metalloproteinase, disintegrin-like, epidermal growth factor-like, cysteine-rich and transmembrane domains, and a cytoplasmic tail, allows ADAM-12 to promote matrix degradation, cell-cell adhesion, and intracellular signaling capacities and thereby to play a critical role in cancer growth and metastasis. Despite ample evidence linking increased ADAM-12 expression with cancer, the mechanisms controlling its upregulation are still unknown.

Antioxidant liposomes protect against CEES-induced lung injury by decreasing SAF-1/MAZ-mediated inflammation in the guinea pig lung.

We reported earlier in a guinea pig model that exposure of 2-chloroethyl ethyl sulfide (CEES), a mustard gas analog, causes lung injury associated with the activation of tumor necrosis factor alpha (TNF-alpha), mitogen activated protein kinases (MAPK) signaling, and activator protein-1 (AP-1) transcription factor. Our earlier studies also revealed that antioxidant liposomes can be used as antidotes. Proinflammatory cytokines IL-1, IL-6, and TNF-alpha, either alone or in combination, can induce the activation of another group of transcription factors, namely SAF-1 (serum accelerator factor-1)/MAZ (Myc-associated zinc finger protein).

SAF-3, a novel splice variant of the SAF-1/MAZ/Pur-1 family, is expressed during inflammation.

The Cys2His2-type zinc finger transcription factor serum amyloid A activating factor 1 [SAF-1, also known as MAZ (myc-associated zinc finger protein) or Pur-1 (purine binding factor-1)] plays an important role in regulation of a variety of inflammation-responsive genes. An SAF-2 splice variant acting as a negative regulator of SAF-1 was identified previously, and the present study reports the identification of a novel SAF-3 splice variant that is expressed during inflammation. SAF-3 mRNA, isolated from a cDNA library produced from IL-1beta-induced cells, originates from a previously unknown first coding exon, and thereby contains a unique N-terminal domain but shares the same six zinc finger DNA-binding domains as present in SAF-1.

Transcriptional synergy mediated by SAF-1 and AP-1: critical role of N-terminal polyalanine and two zinc finger domains of SAF-1.

Previously we determined that inflammation responsive transcription factors AP-1 and SAF-1 synergistically regulate transcriptional induction of the MMP-1 gene. The present study investigated the underlying molecular mechanism of cooperativity between these two different groups of transcription factors. We present evidence that knockdown of SAF-1 by small interfering RNAs inhibits AP-1-mediated increase of human MMP-1 expression.

An inflammation-responsive transcription factor in the pathophysiology of osteoarthritis.

A number of risk factors including biomechanical stress on the articular cartilage imposed by joint overloading due to obesity, repetitive damage of the joint tissues by injury of the menisci and ligaments, and abnormal joint alignment play a significant role in the onset of osteoarthritis (OA). Genetic predisposition can also lead to the formation of defective cartilage matrix because of abnormal gene expression in the cartilage-specific cells. Another important biochemical event in OA is the consequence of inflammation.

Vascular endothelial growth factor expression in arthritic joint is regulated by SAF-1 transcription factor.

Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of arthritis by promoting angiogenesis in the synovial joint and infiltration of inflammatory cells in the synovial joint. Although ample information has been obtained on the mechanism of VEGF regulation during cancer and hypoxic condition, less is known about the control of VEGF expression during arthritis. From the studies on the experimentally induced arthritis in a transgenic mouse model that overexpresses a transcription factor, serum amyloid A activating factor-1 (SAF-1), leading to markedly higher levels of angiogenesis, synovial inflammation, and inflammatory cell infiltration, we have identified a novel mechanism of VEGF regulation.

Inflammation-responsive transcription factor SAF-1 activity is linked to the development of amyloid A amyloidosis.

Abundantly expressed serum amyloid A (SAA) protein under chronic inflammatory conditions gives rise to insoluble aggregates of SAA derivatives in multiple organs resulting in reactive amyloid A (AA) amyloidosis, a consequence of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, familial Mediterranean fever, and Castleman's disease. An inflammation-responsive transcription factor, SAF (for SAA activating factor), has been implicated in the sustained expression of amyloidogenic SAA under chronic inflammatory conditions. However, its role in the pathogenesis of AA amyloidosis has thus far remained obscure.

Inflammation-responsive transcription factors SAF-1 and c-Jun/c-Fos promote canine MMP-1 gene expression.

Matrix metalloproteinase-1 (MMP-1) has been implicated in the pathogenesis of osteoarthritis (OA) due to its ability to degrade extracellular matrix component of the joint cartilage tissue that cushions the bone from frictional damage. Canine hip dysplasia, a developmental orthopedic disease which results in arthritic condition as is seen in human OA is an excellent system to study the involvement of MMP-1 in the pathogenesis of OA. To date, however, no report is available regarding canine MMP-1 promoter and the regulatory mechanism by which increased synthesis of MMP-1 protein might be regulated.

Expression of serum amyloid A transcripts in human trophoblast and fetal-derived trophoblast-like choriocarcinoma cells.

The placenta comprises a highly specialized trophoblast layer, which arises from the embryo and differentiates during embryonic development to perform specialized functions, e.g., synthesis of pregnancy-associated hormones, growth factors and cytokines.

Transcriptional induction of matrix metalloproteinase-9 in the chondrocyte and synoviocyte cells is regulated via a novel mechanism: evidence for functional cooperation between serum amyloid A-activating factor-1 and AP-1.

Increased expression of matrix metalloproteinase-9 (MMP-9) by IL-1beta and TNF-alpha is regarded as a key factor in the degradation of cartilage during arthritis. However, the underlying molecular mechanism of this induction process especially in the cells of the joint capsule remains elusive. Chondrocytes and synoviocytes, the resident cells of joint capsule, markedly increase transcription of MMP-9 in response to IL-1beta- and TNF-alpha-mediated stimulation.

Induction of the MMP-14 gene in macrophages of the atherosclerotic plaque: role of SAF-1 in the induction process.

Based on epidemiological and pathological studies, it is becoming increasingly clear that matrix metalloproteinases (MMPs) play an important role in the pathogenesis of atherosclerosis by participating in vascular remodeling, smooth muscle cell migration, and plaque disruption. MMP-14, because of its unique ability to cause pericellular degradation, its broad substrate specificity, its synthesis in an active form, and its ability to activate other matrix metalloproteinases, is recognized as a prominent member of this family. MMP-14 is detected at high levels in the atherosclerotic plaque.

Transcriptional activity of serum amyloid A-activating factor-1 is regulated by distinct functional modules.

Serum amyloid A-activating transcription factor-1 (SAF-1) plays a major role in regulating transcription of several inflammation-responsive genes, including SAA and matrix metalloproteinase-1, that are implicated in the pathogenesis of reactive secondary amyloidosis, atherosclerosis, and arthritis. SAF-1 is a 477-amino acid protein with six zinc fingers. Its activation during inflammatory condition by a phosphorylation event that leads to an altered structure suggested possible structural modification of this protein as a leading cause of higher activity.

Serum amyloid A-activating factor-1 (SAF-1) transgenic mice are prone to develop a severe form of inflammation-induced arthritis.

The transcription factor serum amyloid A-activating factor-1 (SAF-1) has been identified as a regulator of a number of cellular genes. To assess the pleiotropic role of SAF-1 in vivo, we generated SAF-1 transgenic mice, in which CMV immediate-early promoter was used to direct expression of the SAF-1 transgene in multiple organs. Our study shows that overexpression of SAF-1 predisposes animals to arthritis.

Overexpression of serum amyloid A-activating factor 1 inhibits cell proliferation by the induction of cyclin-dependent protein kinase inhibitor p21WAF-1/Cip-1/Sdi-1 expression.

Inflammation-responsive transcription factor, serum amyloid A-activating factor 1 (SAF-1), has been shown to regulate several genes, including serum amyloid A, gamma-fibrinogen, and matrix metalloproteinase 1, whose abnormal expression is associated with the pathogenesis of arthritis, atherosclerosis, and amyloidosis. Prolonged high level expression of SAF-1 in cultured cells failed to produce any stable cell line that overexpresses SAF-1. To test the fate of SAF-1-overexpressing cells, the cells were monitored for growth and morphological changes over time.

Protein kinase A signaling pathway regulates transcriptional activity of SAF-1 by unmasking its DNA-binding domains.

Serum amyloid A (SAA) activating factor-1 (SAF-1) is an inducible transcription factor that plays a key role in the regulation of several inflammation-responsive genes including SAA and matrix metalloproteinase-1. Increased synthesis of SAA and matrix metalloproteinase-1 is associated with pathogenesis of several diseases including amyloidosis, arthritis, and atherosclerosis. Previously, we showed in vivo interaction of SAF-1 and protein kinase A (PKA) and presented evidence for induction of SAF-1-regulated genes by a PKA signaling pathway.