Urokinase Expression by Tumor Suppressor Protein p53

Shetty, Praveenkumar; Velusamy, Thirunavukkarasu; Bhandary, Yashodhar P.; Shetty, Rashmi S.; Liu, Ming Cheh; Shetty, Sreerama

doi:10.1165/rcmb.2007-0406oc

Cited by 25 publications

(31 citation statements)

References 43 publications

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“…To clarify if LPS treatment alters p53-induced inhibition of uPA expression, we exposed naïve p53-deficient cells or p53-deficient cells transfected with vector DNA or p53 cDNA to PBS, LPS or the amino-terminal fragment (ATF) of uPA for 24 h. The conditioned media were analyzed for uPA by Western blotting. Consistent with our earlier report, (26) reintroduction of p53 in p53-deficient cells inhibited uPA expression. However, treatment with either LPS or ATF, which mimics full length uPA in terms of uPA expression, partially reversed the inhibitory effects of p53 (Fig 6C).…”

Section: Resultssupporting

confidence: 93%

“…We recently reported that tumor suppressor protein, p53 inhibits uPA expression through destabilization of uPA mRNA. (26) The process involves sequence specific interaction of p53 with a 35 nucleotide destabilization determinant present in the uPA mRNA 3′UTR. Previous studies (27–28) suggested that p53 and RRM2 directly interact to control ribonucleotide reductase activity during DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Urokinase Expression at the Posttranscription Level by Lung Epithelial Cells

Shetty¹,

Marudamuthu²,

Abernathy³

et al. 2011

Biochemistry

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Urokinase-type plasminogen activator (uPA) is expressed by lung epithelial cells and regulates fibrin turnover and epithelial cell viability. PMA, LPS, and TNF-alpha, as well as uPA itself, induce uPA expression in lung epithelial cells. PMA, LPS, and TNF-alpha induce uPA expression through increased synthesis as well as stabilization of uPA mRNA, while uPA increases its own expression solely through uPA mRNA stabilization. The mechanism by which lung epithelial cells regulate uPA expression at the level of mRNA stability is unclear. To elucidate this process, we sought to characterize protein-uPA mRNA interactions that regulate uPA expression. Regulation of uPA at the level of mRNA stability involves the interaction of a ~40 kDa cytoplasmic-nuclear shuttling protein with a 66 nt uPA mRNA 3′UTR sequence. We purified the uPA mRNA 3′UTR binding protein and identified it as ribonucleotide reductase M2 (RRM2). We expressed recombinant RRM2 and confirmed its interaction with a specific 66 nt uPA 3′UTR sequence. Immunoprecipitation of cell lysates with anti-RRM2 antibody and RT-PCR for uPA mRNA confirmed that RRM2 binds to uPA mRNA. Treatment of Beas2B cells with uPA or LPS attenuated RRM2-endogenous uPA mRNA interactions, while overexpression of RRM2 inhibited uPA protein and mRNA expression through destabilization of uPA mRNA. LPS exposure of lung epithelial cells translocates RRM2 from the cytoplasm to the nucleus in a time-dependent manner leading to stabilization of uPA mRNA. This newly recognized pathway could influence uPA expression and a broad range of uPA-dependent functions in lung epithelial cells in the context of lung inflammation and repair.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Regulation of Urokinase Expression at the Posttranscription Level by Lung Epithelial Cells

Shetty¹,

Marudamuthu²,

Abernathy³

et al. 2011

Biochemistry

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“…Different mechanisms were therefore proposed; p53 may negatively regulate uPA promoter by interaction with remote enhancer binding factors (Kunz et al, 1995) or p53 may directly bind to the uPA mRNA 3 0 -UTR (Shetty et al, 2008). This study provides another explanation that p53 may act through miR-23b to regulate uPA in human cervical cancer as p53 knockdown reduces miR-23b expression and elevates uPA expression in SiHa cells (data not shown).…”

Section: Hpv-16 E6 Downregulation Of Mir-23b CL Au Yeung Et Almentioning

confidence: 80%

Human papillomavirus type 16 E6 induces cervical cancer cell migration through the p53/microRNA-23b/urokinase-type plasminogen activator pathway

et al. 2011

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Deregulation of microRNA (miRNA or miR) expression in human cervical cancer is associated frequently with human papillomavirus (HPV) integration. miR-23b is often downregulated in HPV-associated cervical cancer. Interestingly, urokinase-type plasminogen activator (uPA), the miR-23b target, is detected in cervical cancer, but not in normal cervical tissues. Thus, the importance of miR-23b and uPA in HPV-associated cervical cancer development is investigated. In this study, the high-risk subtype HPV-16 E6 oncoprotein was found to decrease the expression of miR-23b, increase the expression of uPA, and thus induce the migration of human cervical carcinoma SiHa and CaSki cells. uPA is the target gene for miR-23b as the miR repressed uPA expression and interacted with the 3 0 -untranslated region of uPA mRNA. The tumor suppressor p53 is known to be inactivated by HPV-16 E6. A consensus p53 binding site is detected in the promoter region of miR-23b, whereas p53 transactivated and also interacted with the miR's promoter. Therefore, p53 is believed to mediate the HPV-16 E6 downregulation of miR-23b. From the above, miR-23b/ uPA are confirmed to be involved in HPV-16 E6-associated cervical cancer development.

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“…67 PAI-1 expression is disproportionately increased in injured lungs 33 and also induced by TGF-b, 23 which in turn irreversibly suppresses both uPA activity and its steady-state level by PAI1emediated turnover of the uPAeuPAR complex. The protective effects of increased uPA and uPAR may involve suppression of PAI-1 through increased uPA-and uPARmediated turnover of PAI-1 protein, 47 or inhibition of p53 expression and reversal of p53-mediated induction of PAI-1 expression by increased uPA and uPAR, 7,44,51,52 or both.…”

Section: Upa-fibrinolytic System In Atii Cell Emtmentioning

confidence: 99%

Role of the Urokinase-Fibrinolytic System in Epithelial–Mesenchymal Transition during Lung Injury

Marudamuthu

Bhandary

Shetty

et al. 2015

The American Journal of Pathology

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Alveolar type II epithelial (ATII) cell injury precedes development of pulmonary fibrosis. Mice lacking urokinase-type plasminogen activator (uPA) are highly susceptible, whereas those deficient in plasminogen activator inhibitor (PAI-1) are resistant to lung injury and pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) has been considered, at least in part, as a source of myofibroblast formation during fibrogenesis. However, the contribution of altered expression of major components of the uPA system on ATII cell EMT during lung injury is not well understood. To investigate whether changes in uPA and PAI-1 by ATII cells contribute to EMT, ATII cells from patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, and mice with bleomycin-, transforming growth factor β-, or passive cigarette smoke-induced lung injury were analyzed for uPA, PAI-1, and EMT markers. We found reduced expression of E-cadherin and zona occludens-1, whereas collagen-I and α-smooth muscle actin were increased in ATII cells isolated from injured lungs. These changes were associated with a parallel increase in PAI-1 and reduced uPA expression. Further, inhibition of Src kinase activity using caveolin-1 scaffolding domain peptide suppressed bleomycin-, transforming growth factor β-, or passive cigarette smoke-induced EMT and restored uPA expression while suppressing PAI-1. These studies show that induction of PAI-1 and inhibition of uPA during fibrosing lung injury lead to EMT in ATII cells.

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Urokinase Expression by Tumor Suppressor Protein p53

Cited by 25 publications

References 43 publications

Regulation of Urokinase Expression at the Posttranscription Level by Lung Epithelial Cells

Regulation of Urokinase Expression at the Posttranscription Level by Lung Epithelial Cells

Human papillomavirus type 16 E6 induces cervical cancer cell migration through the p53/microRNA-23b/urokinase-type plasminogen activator pathway

Role of the Urokinase-Fibrinolytic System in Epithelial–Mesenchymal Transition during Lung Injury

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