Phorbol myristate acetate transactivates the avian β3 integrin gene and induces αvβ3 integrin expression

Zhu, Hui Jun; Ross, F. Patrick; Cao, Xu; Teitelbaum, Steven L.

doi:10.1002/(sici)1097-4644(19960601)61:3<420::aid-jcb9>3.0.co;2-v

Cited by 6 publications

(2 citation statements)

References 23 publications

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“…Previous report demonstrated that TPA may upregulate alpha v beta 3 integrin expression in an AP-1 dependent manner [160]. Also, transforming growth factor-beta may up-regulates integrin subunit expression via Smad and Ets signaling [161,162].…”

Section: Expression Of Genes Regulated By Ros For In Emt and Migrationmentioning

confidence: 97%

The signaling mechanism of ROS in tumor progression

2006

Cancer Metastasis Rev

671

489

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Reactive oxygen species (ROS) are recently proposed to be involved in tumor metastasis which is a complicated processes including epithelial-mesenchymal transition (EMT), migration, invasion of the tumor cells and angiogenesis around the tumor lesion. ROS generation may be induced intracellularly, in either NADPH oxidase- or mitochondria-dependent manner, by growth factors and cytokines (such as TGFbeta and HGF) and tumor promoters (such as TPA) capable of triggering cell adhesion, EMT and migration. As a signaling messenger, ROS are able to oxidize the critical target molecules such as PKC and protein tyrosine phosphates (PTPs), which are relevant to tumor cell invasion. PKC contain multiple cysteine residues that can be oxidized and activated by ROS. Inactivation of multiple PTPs by ROS may relieve the tyrosine phosphorylation-dependent signaling. Two of the down-stream molecules regulated by ROS are MAPK and PAK. MAPKs cascades were established to be a major signal pathway for driving tumor cell metastasis, which are mediated by PKC, TGF-beta/Smad and integrin-mediated signaling. PAK is an effector of Rac-mediated cytoskeletal remodeling that is responsible for cell migration and angiogenesis. There are several transcriptional factors such as AP1, Ets, Smad and Snail regulating a lot of genes relevant to metastasis. AP-1 and Smad can be activated by PKC activator and TGF-beta1, respectively, in a ROS dependent manner. On the other hand, Est-1 can be upregulated by H2O2 via an antioxidant response element in the promoter. The ROS-regulated genes relevant to EMT and metastasis include E-cahedrin, integrin and MMP. Comprehensive understanding of the ROS-triggered signaling transduction, transcriptional activation and regulation of gene expressions will help strengthen the critical role of ROS in tumor progression and devising strategy for chemo-therapeutic interventions.

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Section: Expression Of Genes Regulated By Ros For In Emt and Migrationmentioning

confidence: 97%

The signaling mechanism of ROS in tumor progression

2006

Cancer Metastasis Rev

671

489

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“…Expression of the α v β 3 integrin is regulated by expression of the β 3 subunit during osteoclast differentiation (Kitazawa et al, 1995;Li et al, 1995;Zhu et al, 1996). We have previously shown that IL-4-dependent expression of the α v β 3 integrin, in osteoclast precursors is mediated by expression of the β 3 gene (Kitazawa et al, 1995) and, using β 3 gene promoter-reporter constructs, we have demonstrated that IL-4 dependent upregulation is directly mediated by the transcription factor STAT-6 (McHugh et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

NFATc1 regulation of the human β3 integrin promoter in osteoclast differentiation

Crotti

Flannery

Walsh

et al. 2006

Gene

144

103

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The transcription factor NFATc1 plays an essential role in transducing signals from RANKL in osteoclast differentiation. To date, however, the specific transcriptional targets of NFATc1 are unknown. Expression of the beta3 integrin is required for normal osteoclast function. We therefore examined the role of NFATc1 in human beta3 integrin expression in osteoclast differentiation. Analysis of the mouse and human beta3 gene promoters revealed considerable sequence homology across a 1.3 kb region upstream of the transcription start site (TSS), with conserved NFAT binding elements present. The region -1242 to +29 (relative to the TSS) was cloned as a luciferase reporter construct (pB3-1.3) and a deletion construct removing to -997 (pB3-1) made. The deletion of 245 bp 5' removed three conserved NFAT sites including a consensus NFAT:AP-1 site. The pB3-1.3 reporter construct was induced by treatment with RANKL in the range 2.5-40 ng/ml and dose-dependently induced by co-transfection with human NFATc1 in RAW264.7 cells. The pB3-1 deletion construct was minimally induced with RANKL treatment and unresponsive to co-transfected NFATc1. Direct NFAT binding to two of the consensus NFAT sites within this 245 bp 5' region was demonstrated by EMSA and supershift with anti-NFAT antibodies. Mutation of two of the conserved NFAT sites in the -1242 to -997 fragment was required to prevent binding. The double NFAT mutant, in the context of the full-length promoter was unresponsive to RANKL treatment or co-transfected NFATc1. We generated cell-permeable TAT-dominant-negative (dn)NFATc1 fusion proteins to assess the effect of blockade of NFAT signaling. Transduction with dnNFAT inhibited RANKL induction of the human beta3 integrin promoter. Involvement of the NFATc1-calcineurin pathway in regulating the human beta3 integrin promoter was further confirmed using the calcineurin pathway inhibitory peptide 11R-VIVIT. Together these results establish the beta3 gene as a direct target of NFATc1 in RANKL-dependent osteoclast formation.

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PU.1 and NFATc1 mediate osteoclastic induction of the mouse β₃ integrin promoter

Crotti

Sharma

Fleming

et al. 2008

Journal Cellular Physiology

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Expression of the alpha(v)beta(3) integrin is required for normal osteoclast function. We previously showed that an evolutionary conserved NFATc1 binding site is required for RANKL induction and NFATc1 transactivation of the human beta(3) promoter. The mechanism conferring specificity for RANKL induction and NFATc1 transduction of the beta(3) gene in osteoclast differentiation is unclear since NFATc1 is expressed and activated in numerous cell types that do not express the beta(3) gene. PU.1 is an ETS family transcription factor in myeloid cells associated with expression of various osteoclast genes. The present study investigates the role of NFATc1 in concert with PU.1 in osteoclast-specific transcription of the mouse beta(3) integrin gene. The mouse beta(3) promoter was transactivated by NFATc1 in RAW264.7 cells and deletion or mutation of either of the conserved NFAT and PU.1 binding sites abrogated transactivation. NFATc1 transactivation of the mouse beta(3) promoter was specifically dependent on co-transfected PU.1 in HEK293 cells, to the exclusion of other ETS family members. Direct binding of NFATc1 and PU.1 to their cognate sequences was demonstrated by EMSA and NFATc1 and PU.1 occupy their cognate sites in RANKL-treated mouse marrow precursors in chromatin immuno-precipitation (ChIP) assays. TAT-mediated transduction with dominant-negative NFATc1 dose-dependently blocked endogenous expression of the mouse beta(3) integrin and the formation of TRAP positive multinucleated cells in RANKL-treated mouse macrophages. These data provide evidence that NFATc1, in concert with PU.1, are involved in regulation of beta(3) integrin expression during osteoclast differentiation and suggest that PU.1 confers specificity to the NFATc1 response to macrophage lineage cells.

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Phorbol myristate acetate transactivates the avian β3 integrin gene and induces αvβ3 integrin expression

Cited by 6 publications

References 23 publications

The signaling mechanism of ROS in tumor progression

The signaling mechanism of ROS in tumor progression

NFATc1 regulation of the human β3 integrin promoter in osteoclast differentiation

PU.1 and NFATc1 mediate osteoclastic induction of the mouse β₃ integrin promoter

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Phorbol myristate acetate transactivates the avian β3 integrin gene and induces αvβ3 integrin expression

Cited by 6 publications

References 23 publications

The signaling mechanism of ROS in tumor progression

The signaling mechanism of ROS in tumor progression

NFATc1 regulation of the human β3 integrin promoter in osteoclast differentiation

PU.1 and NFATc1 mediate osteoclastic induction of the mouse β3 integrin promoter

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PU.1 and NFATc1 mediate osteoclastic induction of the mouse β₃ integrin promoter