Interaction of BIR2/3 of XIAP with E2F1/Sp1 Activates MMP2 and Bladder Cancer Invasion by Inhibiting Src Translation

AbstractAlthough X-linked inhibitor of apoptosis protein (XIAP) is associated with cancer cell behaviors, the structure-based function of XIAP in promotion human bladder cancer (BC) invasion is barely explored. Herein, we discovered that ectopic expression of the BIR domains of XIAP rescued the MMP2 activation and invasion in XIAP-deleted BC cells, while Src was further defined as a XIAP downstream negative regulator for MMP2 activation and BC invasion. The inhibition of Src expression by BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation resulting from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, consequently leading to fully activation of E2F1/Sp1. Our findings provide a novel insight into understanding of specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.

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XIAP Interaction with E2F1 and Sp1 via its BIR2 and BIR3 domains specific activated MMP2 to promote bladder cancer invasion

Oncogenesis ◽

10.1038/s41389-019-0181-8 ◽

2019 ◽

Vol 8 (12) ◽

Cited By ~ 4

Author(s):

Jiheng Xu ◽

Xiaohui Hua ◽

Rui Yang ◽

Honglei Jin ◽

Jingxia Li ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Invasion ◽

Feedback Loop ◽

Ectopic Expression ◽

Direct Interaction ◽

Protein Translation ◽

Negative Regulator ◽

Cancer Cell Invasion ◽

Design Synthesis ◽

First Time

AbstractXIAP has generally been thought to function in bladder cancer. However, the potential function of structure-based function of XIAP in human BC invasion has not been well explored before. We show here that ectopic expression of the BIR domains of XIAP specifically resulted in MMP2 activation and cell invasion in XIAP-deleted BC cells, while Src was further defined as an XIAP downstream negative regulator for MMP2 activation and BC cell invasion. The inhibition of Src expression by the BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation; which was resulted from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, respectively. The interaction of BIR2/BIR3 with E2F1/Sp1 unexpectedly occurred, which could be blocked by serum-induced XIAP translocation. Taken together, our studies, for the first time revealed that: (1) BIR2 and BIR3 domains of XIAP play their role in cancer cell invasion without affecting cell migration by specific activation of MMP2 in human BC cells; (2) by BIR2 interacting with E2F1 and BIR3 interacting with Sp1, XIAP initiates E2F1/Sp1 positive feedback loop-dependent transcription of miR-203, which in turn inhibits Src protein translation, further leading to MMP2-cleaved activation; (3) XIAP interaction with E2F1 and Sp1 is observed in the nucleus. Our findings provide novel insights into understanding the specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.

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Gefitinib Reverses TRAIL Resistance in Human Bladder Cancer Cell Lines via Inhibition of AKT-Mediated X-Linked Inhibitor of Apoptosis Protein Expression

Cancer Research ◽

10.1158/0008-5472.can-06-1224 ◽

2007 ◽

Vol 67 (4) ◽

pp. 1430-1435 ◽

Cited By ~ 60

Author(s):

Marissa Shrader ◽

Maria Simona Pino ◽

Laura Lashinger ◽

Menashe Bar-Eli ◽

Liana Adam ◽

...

Keyword(s):

Bladder Cancer ◽

Protein Expression ◽

Cell Lines ◽

Inhibitor Of Apoptosis ◽

Human Bladder Cancer ◽

Human Bladder ◽

Inhibitor Of Apoptosis Protein ◽

Human Bladder Cancer Cell ◽

Apoptosis Protein ◽

Trail Resistance

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Decreased c-Myc mRNA Stability via the MicroRNA 141-3p/AUF1 Axis Is Crucial for p63α Inhibition of Cyclin D1 Gene Transcription and Bladder Cancer Cell Tumorigenicity

Molecular and Cellular Biology ◽

10.1128/mcb.00273-18 ◽

2018 ◽

Vol 38 (21) ◽

Cited By ~ 5

Author(s):

Xin Li ◽

Zhongxian Tian ◽

Honglei Jin ◽

Jiheng Xu ◽

Xiaohui Hua ◽

...

Keyword(s):

Bladder Cancer ◽

Cyclin D1 ◽

Gene Transcription ◽

Mrna Stability ◽

Rna Binding ◽

D1 Protein ◽

Protein Translation ◽

The United States ◽

Negative Regulator ◽

Anchorage Independent Growth

ABSTRACTBladder cancer (BC) ranks as the sixth most common cancer in the United States and is the leading cause of death in patients with urinary malignancies. p63 is a member of the p53 family and is believed to function as a tumor suppressor in human BCs. Our most recent studies revealed a previously unknown function of the RING of XIAP in promoting microRNA 4295 (miR-4295) transcription, thereby reducing p63α protein translation and enhancing normal urothelial transformation, whereas p63α upregulates hsp70 transcription, subsequently activating the HSP70/Wasf3/Wave3/matrix metalloproteinase 9 (MMP-9) axis and promoting BC cell invasion via initiating the transcription factor E2F1. In this study, we found that p63α inhibited cyclin D1 protein expression, subsequently decreasing the ability of BC cell anchorage-independent growthin vitroand tumorigenicityin vivo. Mechanistic studies demonstrated that p63α expression is able to downregulate cyclin D1 gene transcription through attenuation of c-Myc mRNA stability. We further show that the reduction of miR-141-3p expression by p63α directly releases its inhibition of 3′ untranslated region (UTR) activity of AU-rich element RNA-binding factor 1 (AUF1) mRNA, thereby increasing AUF1 protein translation and further resulting in degradation of c-Myc mRNA, which, in turn, reduces cyclin D1 gene transcription and BC cell anchorage-independent growth. Collectively, our results demonstrate that p63α is a negative regulator of BC cell tumorigenic growth, a distinctly different function than its promotion of BC invasion, thus providing further new insight into the “two faces” of p63α in regulation of BC cell tumorigenic growth and progression/invasion.

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Germ layer-specific regulation of cell polarity and adhesion gives insight into the evolution of mesoderm

eLife ◽

10.7554/elife.36740 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 16

Author(s):

Miguel Salinas-Saavedra ◽

Amber Q Rock ◽

Mark Q Martindale

Keyword(s):

Cell Adhesion ◽

Cell Polarity ◽

Ectopic Expression ◽

Par Proteins ◽

Cell Behaviors ◽

Cnidarian Nematostella Vectensis ◽

Distinct Cell ◽

Transcription Factor Genes ◽

Specific Regulation ◽

Insight Into

In triploblastic animals, Par-proteins regulate cell-polarity and adherens junctions of both ectodermal and endodermal epithelia. But, in embryos of the diploblastic cnidarian Nematostella vectensis, Par-proteins are degraded in all cells in the bifunctional gastrodermal epithelium. Using immunohistochemistry, CRISPR/Cas9 mutagenesis, and mRNA overexpression, we describe the functional association between Par-proteins, ß-catenin, and snail transcription factor genes in N. vectensis embryos. We demonstrate that the aPKC/Par complex regulates the localization of ß-catenin in the ectoderm by stabilizing its role in cell-adhesion, and that endomesodermal epithelial cells are organized by a different cell-adhesion system than overlying ectoderm. We also show that ectopic expression of snail genes, which are expressed in mesodermal derivatives in bilaterians, is sufficient to downregulate Par-proteins and translocate ß-catenin from the junctions to the cytoplasm in ectodermal cells. These data provide molecular insight into the evolution of epithelial structure and distinct cell behaviors in metazoan embryos.

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