Disease relevance of Sat1

• In attempts to clarify the function of SSAT in tumour development, we have utilized the Apc(Min/+) mouse, which carries a mutant allele of the Apc (adenomatous polyposis coli) gene, rendering it susceptible to the formation of multiple adenomas in the small intestine and colon [1].
• In contrast, the combination of N(1), N(11)-diethylnorspermine with MDL72527 dramatically activated SSAT, causing profound depletion of pancreatic polyamines and acute pancreatitis [2].
• Overall, the findings reveal meaningful antitumor activity by BENSPM against 2 human melanoma xenografts and provide in vivo evidence consistent with SSAT-induced polyamine depletion playing a determining role in at least the initial phase of the antitumor response [3].
• Although most polyamine-based anticancer strategies target biosynthesis, we recently showed that activation of polyamine catabolism at the level of spermidine/spermine N(1)-acetyltransferase-1 (SSAT) suppresses tumor outgrowth in a mouse prostate cancer model [4].
• The finding that deletion of SSAT reduces tumorigenesis suggests that small-molecule inhibition of the enzyme may represent a nontoxic prevention and/or treatment strategy for gastrointestinal cancers [4].

High impact information on Sat1

• Using yeast two-hybrid screening, we identified the polyamine catabolizing enzyme spermidine/spermine N(1)-acetyltransferase (SSAT) as a specific binding partner of the alpha9 cytoplasmic domain [5].
• Overexpression of SSAT increased alpha9beta1-mediated migration, and small interfering RNA knockdown of SSAT inhibited this migration without affecting cell adhesion or migration that was mediated by other integrin cytoplasmic domains [5].
• Administration of zinc resulted in a marked induction of pancreatic SSAT, overaccumulation of putrescine, and appearance of N(1)-acetylspermidine with extensive depletion of spermidine and spermine in transgenic animals [2].
• Induction of SSAT by the polyamine analogue N(1),N(11)-diethylnorspermine reduced pancreatic polyamines levels only moderately and without signs of organ inflammation [2].
• To investigate the physiological function SSAT, we generated a transgenic rat line overexpressing the SSAT gene under the control of the inducible mouse metallothionein I promoter [2].

Chemical compound and disease context of Sat1

• TRAMP (transgenic adenocarcinoma of mouse prostate) female C57BL/6 mice carrying the SV40 early genes (T/t antigens) under an androgen-driven probasin promoter were cross-bred with male C57BL/6 transgenic mice that systemically overexpress SSAT [6].
• Greater analog toxicity in transgenic animals may be attributable to higher tissue levels of DENSPM facilitated by SSAT-mediated decreases in spermidine and spermine [7].
• These results support our earlier findings indicating that elevated concentrations of brain putrescine, irrespective whether derived from an overexpression of ornithine decarboxylase, or as shown here, from an overexpression of SSAT, play in all likelihood a neuroprotective role in brain injury [8].
• We have shown that SSAT activity and SSAT mRNA are significantly induced by antifolate CB 3717 and folate that evoke a drug-injury-dependent hyperplasia [9].
• N(1),N(11)-Diethylnorspermine, a powerful inducer of SSAT, inhibited liver weight gain and proliferative activity in both syngenic and transgenic rats [10].

Biological context of Sat1

• Influence of testosterone on regulation of ODC, antizyme, and N1-SSAT gene expression in mouse kidney [11].
• In addition, we show that the Hyp deletion does not involve the downstream spermidine/spermine N1-acetyl transferase (Sat; formerly Ssat) gene and thus is not a contiguous gene deletion syndrome [12].
• When MIN mice were crossed with SSAT knock-out mice, they developed 75% fewer adenomas in the small intestine, suggesting that under basal conditions, SSAT contributes significantly to the MIN phenotype [4].
• Since the two fibroblasts were genetically identical except for the transgene, the various metabolic and growth response differences are directly attributable to overexpression of SSAT [13].
• These results indicated that SSAT does not play a major role in the maintenance of polyamine homeostasis, and the toxicity exerted by polyamine analogues is largely not based on SSAT-induced depletion of the natural polyamines [14].

Anatomical context of Sat1

• SSAT activity in the nontransgenic fibroblasts increased approximately 200-fold [13].
• Moreover, embryonic stem cells appear to operate an SSAT-independent system for the back-conversion of spermine to spermidine [14].
• To exclude the possibility that changes in differentiation originated from underlying connective tissue, we introduced SSAT gene into an established rat epidermal cell line [15].
• These results suggest that the cutaneous changes of SSAT Tg animals are due to disorders of the keratinocyte differentiation [15].
• The interaction of the polyamine pathway with the p53-p21 pathway was shown in vitro, where activation of SSAT with polyamine analog or the addition of putrescine to cultured hepatocytes induced the expression of p53 and p21 and decreased cell viability [16].

Associations of Sat1 with chemical compounds

• In comparison with singly transgenic animals overexpressing SSAT, the doubly transgenic mice unexpectedly displayed much more striking signs of activated polyamine catabolism, as exemplified by a massive putrescine accumulation and an extreme reduction of hepatic spermidine and spermine pools [17].
• Testosterone treatment enhanced AZ1 and N1-SSAT mRNA levels in a time-dependent manner by unknown molecular mechanisms [11].
• In particular, the polyamine catabolic enzyme SSAT (spermidine/spermine N(1)-acetyltransferase) seems to have different roles in tumorigenesis, depending upon the particular system being analysed [1].
• The latter led to heightened metabolic flux through the polyamine pathway and an associated approximately 70% reduction in the SSAT cofactor acetyl-CoA and a approximately 40% reduction in the polyamine aminopropyl donor S-adenosylmethionine in TRAMP/SSAT compared with TRAMP prostatic tissue [6].
• In situ hybridization histochemistry experiments showed that the SSAT transcript is expressed only by the epithelial cells of the straight and convoluted distal tubules of the nephron, while the expression of the ODC transcript is confined to the epithelium of the convoluted and straight portion of the proximal tubules [18].

Other interactions of Sat1

• The expression of AZ1 and N1-SSAT mRNA was similar in male and female mouse kidneys [11].
• The data further suggest that SSAT may play a role in the initiation of injury, whereas p21 and stathmin may be involved in the resolution and recovery after liver IRI [16].
• Overexpression of SSAT (polyamine catabolic enzyme) in female mice results in impaired ovarian folliculogenesis and uterine hypoplasia [19].
• The biological tolerance for these compounds was tested in wild-type mice and transgenic mice carrying the metallothionein promoter-driven spermidine/spermine N(1)-acetyltransferase gene (MT-SSAT) [20].
• Catecholamine depletion evoked by reserpine drastically decreases the folate-induced activity of S-adenosylmethionine decarboxylase (AdoMetDC), which limits polyamine biosynthesis, but has no effect on SSAT activity augmented by CB 3717 [9].

Analytical, diagnostic and therapeutic context of Sat1

• In situ hybridization analyses revealed a marked overexpression of SSAT-specific mRNA all over the brain tissue of the transgenic animals [8].
• Castration of male mice for 7 days resulted in a 40% decrease of the renal levels of both SSAT and ODC transcripts [18].
• Northern blots demonstrated that the mRNA levels of SSAT are increased by greater than threefold in the renal cortex and by fivefold in the renal medulla at 12 h and returned to baseline at 48 h after ischemia [21].
• The concentration of putrescine in the kidney increased by approximately 4- and approximately 7.5-fold at 12 and 24 h of reperfusion, respectively, consistent with increased functional activity of SSAT [21].
• SSAT expression was found throughout normal kidney tubules, as detected by nephron segment RT-PCR [21].

References