ERK-dependent Signaling Pathway and Transcriptional Factor Ets-1 Regulate Matrix Metalloproteinase-9 Production in Transforming Growth Factor-β1 Stimulated Glomerular Podocytes

Liu, Senyan; Liang, Yan; Huang, Haichang; Wang, Lizhu; Li, Yongqiang; Li, Jingzi; Li, Xiaomei; Wang, Haiyan

doi:10.1159/000089846

Cited by 36 publications

(36 citation statements)

References 49 publications

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“…TMV from PC3 cells promoted higher migration capacity of fibroblasts than TMV from LnCaP cells, probably in relation with the cellular origin and/or enrichment in MMP-14 observed in TMV from PC3 cells. The implication of the ERK1/2 pathway in pro-MMP-9 expression has been reported by others (30,31). Our results are in agreement with those obtained with platelet MV, described to induce increase of ERK1/2 phosphorylation and MMP-9 release in fibroblasts.…”

Section: Discussionsupporting

confidence: 93%

Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis

et al. 2009

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Tumor microenvironment is enriched in plasma membrane microvesicles (MV) shed from all cell types that constitute the tumor mass, reflecting the antigenic profile of the cells they originate from. Fibroblasts and tumor cells mutually communicate within tumor microenvironment. Recent evidences suggest that tumor-derived MVs (TMV) exert a broad array of biological functions in cell-to-cell communication. To elucidate their role in cancer-to-fibroblast cell communication, TMV obtained from two prostate carcinoma cell lines with high and weak metastatic potential (PC3 and LnCaP, respectively) have been characterized. TMV exhibit matrix metalloproteinases (MMP) and extracellular MMP inducer at their surface, suggesting a role in extracellular matrix degradation. Moreover, TMV not only induce the activation of fibroblasts assessed through extracellular signal-regulated kinase 1/2 phosphorylation and MMP-9 up-regulation, increase motility and resistance to apoptosis but also promote MV shedding from activated fibroblasts able in turn to increase migration and invasion of highly metastatic PC3 cells but not LnCaP cells. PC3 cell chemotaxis seems, at least partially, dependent on membrane-bound CX3CL1/fractalkine ligand for chemokine receptor CX3CR1. The present results highlight a mechanism of mutual communication attributable not only to soluble factors but also to determinants harbored by MV, possibly contributing to the constitution of a favorable niche for cancer development. [Cancer Res 2009;69(3):785-93]

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Section: Discussionsupporting

confidence: 93%

Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis

et al. 2009

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“…In response to serum, ets-1 forms a ternary complex with serum response factor. TGF-␤ also induces ets-1 expression (26). Our data showing that serum depletion decreased whereas TGF-␤ increased miR-192 expression (Fig.…”

Section: Mir-192 Is Expressed In MMC and Up-regulated By Tgf-␤supporting

confidence: 53%

MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressors

Kato¹,

Zhang

Wang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

669

691

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Key features of diabetic nephropathy (DN) include the accumulation of extracellular matrix proteins such as collagen 1-␣ 1 and -2 (Col1a1 and -2). Transforming growth factor ␤1 (TGF-␤), a key regulator of these extracellular matrix genes, is increased in mesangial cells (MC) in DN. By microarray profiling, we noted that TGF-␤ increased Col1a2 mRNA in mouse MC (MMC) but also decreased mRNA levels of an E-box repressor, ␦EF1. TGF-␤ treatment or short hairpin RNAs targeting ␦EF1 increased enhancer activity of upstream E-box elements in the Col1a2 gene. TGF-␤ also decreased the expression of Smad-interacting protein 1 (SIP1), another E-box repressor similar to ␦EF1. Interestingly, we noted that SIP1 is a target of microRNA-192 (miR-192), a key miR highly expressed in the kidney. miR-192 levels also were increased by TGF-␤ in MMC. TGF-␤ treatment or transfection with miR-192 decreased endogenous SIP1 expression as well as reporter activity of a SIP1 3 UTR-containing luciferase construct in MMC. Conversely, a miR-192 inhibitor enhanced the luciferase activity, confirming SIP1 to be a miR-192 target. Furthermore, miR-192 synergized with ␦EF1 short hairpin RNAs to increase Col1a2 E-box-luc activity. Importantly, the in vivo relevance was noted by the observation that miR-192 levels were enhanced significantly in glomeruli isolated from streptozotocin-injected diabetic mice as well as diabetic db/db mice relative to corresponding nondiabetic controls, in parallel with increased TGF-␤ and Col1a2 levels. These results uncover a role for miRs in the kidney and DN in controlling TGF-␤-induced Col1a2 expression by down-regulating E-box repressors.diabetic nephropathy ͉ mesangial cells ͉ small noncoding RNA ͉ transforming growth factor ␤1 D iabetic nephropathy (DN) is the most common cause of kidney failure in patients with diabetes mellitus. The major characteristics of DN include glomerular basement-membrane thickening, mesangial expansion and hypertrophy, and an accumulation of extracellular matrix (ECM) proteins (1). Evidence shows that transforming growth factor ␤1 (TGF-␤) levels are increased under diabetic conditions in renal cells, including mesangial cells (MC), can up-regulate ECM proteins such as collagens (2, 3), and also can promote MC survival and oxidant stress (4).To date, Smad transcription factors have been shown to be the major effectors of TGF-␤ signaling (5, 6). Collagen 1-␣ 1 and -2 (Col1a1 and -2) and other ECM genes are regulated in MC by TGF-␤ via Smads (7,8). The regulation of collagen by TGF-␤ in MC also is mediated by mitogen-activated protein kinases (MAPKs) such as p38 and ERKs (9-11). However, the molecular mechanisms by which TGF-␤ regulates ECM genes still are not understood fully. The collagen gene has E-box elements in the far upstream enhancer region (12, 13). An E-box repressor, ␦EF1, is a key inhibitor of E-cadherin (14) and E2-box transcription factors such as Nkx2.5 (12). Moreover, it is a known repressor of collagen type 1 and type 2 genes in other cells (12, 13), but its role in MC is ...

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“…3A), suggesting that they are important for regulation of MDMX expression. c-Ets-1 and Elk-1 are downstream targets of Ras, regulated via ERK-mediated phosphorylation (15,27). To confirm the function of these sites, point mutations at each of the potential transcription factor binding sites were introduced into the 1.1-kb promoter construct.…”

Section: Resultsmentioning

confidence: 99%

Regulation of MDMX Expression by Mitogenic Signaling

Gilkes

Pan

Coppola³

et al. 2008

Molecular and Cellular Biology

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MDMX is an important regulator of p53 transcriptional activity and stress response. MDMX overexpression and gene amplification are implicated in p53 inactivation and tumor development. Unlike MDM2, MDMX is not inducible by p53, and little is known about its regulation at the transcriptional level. We found that MDMX levels in tumor cell lines closely correlate with promoter activity and mRNA level. Activated K-Ras and insulin-like growth factor 1 induce MDMX expression at the transcriptional level through mechanisms that involve the mitogen-activated protein kinase and c-Ets-1 transcription factors. Pharmacological inhibition of MEK results in down-regulation of MDMX in tumor cell lines. MDMX overexpression was detected in ϳ50% of human colon tumors and showed strong correlation with increased extracellular signal-regulated kinase phosphorylation. Therefore, MDMX expression is regulated by mitogenic signaling pathways. This mechanism may protect normal proliferating cells from p53 but also hamper p53 response during tumor development.MDMX is a p53 binding protein and a regulator of p53 response to DNA damage and ribosomal stress (7,14,19). The physiological importance of MDMX was revealed by the embryonic lethality of MDMX-null mice, which can be rescued by the simultaneous knockout of p53 (13,30,33). MDMX overexpression has been reported in 40% of tumor cell lines (36) and 18.5% of breast, colon, and lung tumor samples (10). It is amplified in 4% of glioblastomas (37) and 5% of breast tumors (10). More recently, ϳ60% of retinoblastomas have been found to have MDMX overexpression or gene amplification (22). MDMX overexpression prevents oncogenic Ras-induced premature senescence in mouse fibroblasts and cooperates with activated Ras to confer tumorigenic potential in nude mice (10). Taken together the evidence suggests that MDMX overexpression can efficiently suppress p53 and may alleviate or delay the selection for p53 mutation during tumor initiation and progression.MDMX is structurally similar to its homolog and binding partner MDM2 (45). Unlike MDM2, which promotes p53 degradation, MDMX does not have significant intrinsic E3 ligase activity (46). MDMX forms heterodimers with MDM2 through C-terminal RING domain interactions (40, 47), which stimulates the ability of MDM2 to ubiquitinate and degrade p53 (16,26). MDM2 can also ubiquitinate itself as well as MDMX. Under nonstress conditions, MDM2 and p53 have short halflives whereas MDMX is relatively stable. Following DNA damage, both p53 and MDM2 are phosphorylated by several kinases (44). Most notably, ATM phosphorylates p53 on serine 15 and enhances its transcriptional activity (2). ATM also activates Chk2, which in turn phosphorylates p53 on serine 20 and inhibits binding to MDM2 (2,6,42,43). ATM phosphorylation of MDM2 also inhibits its ability to degrade p53. The combination of these modifications results in the stabilization and activation of p53.Although MDMX can regulate p53 stability by heterodimerization with MDM2, its impact on p53 level is moderate c...

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ERK-dependent Signaling Pathway and Transcriptional Factor Ets-1 Regulate Matrix Metalloproteinase-9 Production in Transforming Growth Factor-β1 Stimulated Glomerular Podocytes

Cited by 36 publications

References 49 publications

Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis

Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis

MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressors

Regulation of MDMX Expression by Mitogenic Signaling

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