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As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC. [ABSTRACT FROM AUTHOR]

Estrogen receptors (ER) are important transcription factors to relay signals from estrogen and to regulate proliferation of some of breast cancel's. The cycling of estrogen-induced DNA binding and nbiqiiitin-linked proteolysis of ER potentiates ER-mediated transcription. Indeed, several transcriptional coactivators for ER-dependent transcription nbiqnitinate ER. Histone acetyltransferase (HAT) Hbol/KAT7/MYST2, involved in global histone acetylation, DNA replication, transcription, and cellular proliferation, promotes proteasome-dependent degradation of ERα through nbiqnitination. However, molecular mechanism for nbiqiiitination of ER/* by Hbol is unknown. Here we report the intrinsic nbiquitin E3 Ugase activity of Hbol toward the ERαr. The ligand, estradiol-17β, inhibited E3 ligase activity of Hbol for ERα in vitro, whereas hyperactive ERα mutants from metastatic breast cancers resistant to hormonal therapy, were better substrates for ERα nbiqnitination by Hbol. Hbol knock-down caused increase in ERα: expression. Hbol is another ERa coactivator that ubiquitinates ERα. [ABSTRACT FROM AUTHOR]

Saposin D-deficient (Sap-D-/-) mice develop polydipsia/polyuria and die prematurely due to renal failure with robust hydronephrosis. Such symptoms emerged when they were around 3 mo of age. To investigate the pathogenesis of their water mishandling, we attempted to limit water supply and followed sequential changes of physiological and biochemical parameters. We also analyzed renal histological changes at several time points. At 3 mo old just before water restriction challenge was started, their baseline arginine vasopressin level was comparable to the wild-type (WT) level. Twenty-four-hour water deprivation and desamino D-arginine vasopressin administration improved polydipsia and polyuria to certain degrees. However, creatinine concentrations in Sap-D-/- mice were significantly higher than those in WT mice, suggesting that some renal impairment already emerged in the affected mice at this age. Renal histological analyses revealed that renal tubules and collecting ducts were expanded after 3 mo old. After 6 mo old, vacuolar formation was observed, many inflammatory cells migrated around the ducts, and epithelial monolayer cells of tubular origin were replaced by plentiful cysts of various sizes. At 10∼12 mo old, severe cystic deformity appeared. On the other hand, 8-mo-long water restriction started at 4 mo old dramatically improved tubular damage and restored once-dampened amount of tubular aquaporin2 protein to the WT level. Furthermore, 10-molong water restriction ameliorated their renal function. Remarkably, by continuing water restriction thereafter, overall survival period became comparable with that of the WT. Together, polyuria, devastating renal tubular lesions, and renal failure were ameliorated by the mere 10-mo-long water restriction, which would trigger lethal dehydration if the disease were to be caused by any processes other than primary polydipsia. Our study demonstrates that long-term water restriction surely improved renal histopathological changes leading to prevention of premature death in Sap-D-/- mice. [ABSTRACT FROM AUTHOR]

It is known that the cyclin‐dependent kinase inhibitor (CDKI) gene p21Cip1 suppresses rheumatoid inflammation by down‐modulating type I interleukin‐1 receptor (IL‐1RI) expression and inhibiting JNK activity. The purpose of this study was to determine whether CDK activity directly modulates the production of inflammatory molecules in patients with rheumatoid arthritis (RA).Genes for the CDKIs p16INK4a and p18INK4c, a constitutively active form of retinoblastoma (RB) gene product, cyclin D1, and CDK‐4, were transferred into RA synovial fibroblasts (RASFs). RASFs were also treated with a synthetic CDK‐4/6 inhibitor (CDK4I). Levels of matrix metalloproteinase 3 (MMP‐3), monocyte chemoattractant protein 1 (MCP‐1), and IL‐1RI expression were determined by Northern blotting, real‐time polymerase chain reaction analysis, and enzyme‐linked immunosorbent assay. CDKIs were immunoprecipitated to reveal their association with JNK.Transfer of the p16INK4a and p18INK4c genes and CDK4I suppressed the production of MMP‐3 and MCP‐1. Unlike p21Cip1, neither CDKI gene inhibited IL‐1RI or JNK. The expression of MMP‐3 was up‐regulated when CDK‐4 activity was augmented. This regulation functioned at the messenger RNA (mRNA) level in MMP‐3, but not in MCP‐1. Transfer of active RB suppressed the production of MMP‐3 and MCP‐1 without changing their mRNA levels.CDK‐4/6 modulated the production of MMP‐3 and MCP‐1. MMP‐3 production was regulated primarily at the mRNA level in an RB‐independent manner, whereas MCP‐1 production was controlled posttranscriptionally by RB. These results show that cell cycle proteins are associated with control of mediators of inflammation through multiple pathways. [ABSTRACT FROM AUTHOR]