Induction of Apoptosis by a Secreted Lipocalin That is Transcriptionally Regulated by IL-3 Deprivation

Devireddy, Laxminarayana R.; Teodoro, Jose G.; Richard, Fabien; Green, Michael R.

doi:10.1126/science.1061075

Cited by 351 publications

(427 citation statements)

References 32 publications

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“…This hypothesis was furthered strengthened by the observation that NGAL induced the apoptosis of neutrophils through an autocrine pathway (Devireddy et al, 2001). In a recent publication, Tong et al (2005) showed that although NGAL expression is closely associated with apoptosis, it also favours cell survival.…”

Section: Discussionmentioning

confidence: 98%

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia

et al. 2008

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Pancreatic cancer is a highly lethal malignancy with a dismal 5-year survival of less than 5%. The scarcity of early biomarkers has considerably hindered our ability to launch preventive measures for this malignancy in a timely manner. Neutrophil gelatinaseassociated lipocalin (NGAL), a 24-kDa glycoprotein, was reported to be upregulated nearly 27-fold in pancreatic cancer cells compared to normal ductal cells in a microarray analysis. Given the need for biomarkers in the early diagnosis of pancreatic cancer, we investigated the expression of NGAL in tissues with the objective of examining if NGAL immunostaining could be used to identify foci of pancreatic intraepithelial neoplasia, premalignant lesions preceding invasive cancer. To examine a possible correlation between NGAL expression and the degree of differentiation, we also analysed NGAL levels in pancreatic cancer cell lines with varying grades of differentiation. Although NGAL expression was strongly upregulated in pancreatic cancer, and moderately in pancreatitis, only a weak expression could be detected in the healthy pancreas. The average composite score for adenocarcinoma (4.26 ± 2.44) was significantly higher than that for the normal pancreas (1.0) or pancreatitis (1.0) (Po0.0001). Further, although both well-and moderately differentiated pancreatic cancer were positive for NGAL, poorly differentiated adenocarcinoma was uniformly negative. Importantly, NGAL expression was detected as early as the PanIN-1 stage, suggesting that it could be a marker of the earliest premalignant changes in the pancreas. Further, we examined NGAL levels in serum samples. Serum NGAL levels were above the cutoff for healthy individuals in 94% of pancreatic cancer and 62.5% each of acute and chronic pancreatitis samples. However, the difference between NGAL levels in pancreatitis and pancreatic cancer was not significant. A ROC curve analysis revealed that ELISA for NGAL is fairly accurate in distinguishing pancreatic cancer from non-cancer cases (area under curve ¼ 0.75). In conclusion, NGAL is highly expressed in early dysplastic lesions in the pancreas, suggesting a possible role as an early diagnostic marker for pancreatic cancer. Further, serum NGAL measurement could be investigated as a possible biomarker in pancreatitis and pancreatic adenocarcinoma.

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Section: Discussionmentioning

confidence: 98%

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia

et al. 2008

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“…LCN2 encodes lipocalin 2 that can transport metal ions and fat acid (Chu et al, 1998), induce apoptosis (Devireddy et al, 2001), inhibit bacteria growth (Goetz et al, 2002), and regulate inflammatory responses (Cowland and Borregaard, 1997). It has been also reported to participate in the progression of many malignancies such as mammary tumor (Stoesz et al, 1998;Soiland et al, 2009;Yang et al, 2009), digestive tumors (Kubben et al, 2007;Zhang et al, 2007Zhang et al, , 2009), but except lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Screening and Identification of Distant Metastasis‐Related Differentially Expressed Genes in Human Squamous Cell Lung Carcinoma

Wang¹,

Zhou²,

Xiong³

et al. 2012

The Anatomical Record

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Distant metastasis is one of the leading causes of lung cancer death. Detecting the early-stage molecular alternations in primary tumors, such as gene expression differences, provides a ''prognostic'' value to the precaution of tumor metastasis. The aim of this article is to screen and identify the metastasis-related genes in human squamous cell lung carcinoma. Primary tumor tissues of nine patients with subsequent metastasis and eight patients without metastasis were selected to perform the gene microarray experiment. GO and pathway analyses were used to determine the differentially expressed genes. Two identified genes were further validated by real-time quantitative reverse transcription polymerase chain reaction (PCR) (real-time qRT-PCR). Two hundred and thirty-eight differentially expressed genes were detected in gene chip experiment, including 51 up-regulated genes and 187 down-regulated genes. These genes were involved in several cellular processes, including cell adhesion, cell cycle regulation, and apoptosis. GO analysis showed that the differentially expressed genes participated in a wide ranging of metastasis-related processes, including extracellular region and regulation of liquid surface tension. In addition, pathway analysis demonstrated that the differentially expressed genes were enriched in pathways related to cell cycle and Wnt signaling. Real-time qRT-PCR validation experiment of LCN2 and PDZK1IP1 showed a consistent up-regulation in the metastasis group. The metastasis of human squamous cell lung carcinoma is a complex process that is regulated by multiple gene alternations on the expression levels. The 238 differentially expressed genes identified in this study presumably contain a core set of genes involved in tumor metastasis. The real-time qRT-PCR results of PDZK1IP1 and LCN2 validated the reliability of this gene microarray experiment. Anat Rec,

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“…Recently, lipocalin was reported to be transcriptionally regulated by IL-3 deprivation and to induce apoptosis in IL-3-dependent pro-B cells through an autocrine pathway [28]. Although we examined the transcriptional expression of lipocalin during mast cell apoptosis induced by depletion of IL-3, we could not detect it (data not shown), suggesting a cell type-specific regulation of apoptosis.…”

Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

“…Recently, lipocalin, a new apoptosis-inducing molecule, which is transcriptionally regulated by deprivation of IL-3, has been reported [28]. Although the precise mechanisms are unknown, apoptosis induced by lipocalin is also inhibited by overexpression of Bcl-xL, suggesting a critical role for Bcl-xL in the anti-apoptotic effects in IL-3 deprivation-induced apoptosis [28]. In this study, we investigated the mechanisms of caspase-dependent and -independent mast cell apoptosis induced by IL-3 deprivation and its prevention by LPS through TLR4 focusing on the expression of anti-or pro-apoptotic molecules.…”

Section: Introductionmentioning

confidence: 99%

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Caspase‐dependent and ‐independent apoptosis of mast cells induced by withdrawal of IL‐3 is prevented by Toll‐like receptor 4‐mediated lipopolysaccharide stimulation

Yoshikawa

Tasaka

2003

Eur J Immunol

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IL-3-dependent mucosal-like mast cells undergo apoptosis upon withdrawal of IL-3. Generally, the apoptosis is mediated by the activation of caspases and inhibited by addition of the pan-caspase inhibitors z-VAD-FMK or BOC-D-FMK. However, DNA fragmentation, a typical characteristic of apoptosis, is not inhibited by z-VAD-FMK or BOC-D-FMK in mast cell apoptosis. In this study, we demonstrate that the apoptosis of mast cells is mediated by both caspase-dependent and -independent mechanisms. The caspase-independent apoptosis is mediated by the translocation of endonuclease G from mitochondria into nuclei. Withdrawal of IL-3 caused down-regulation of Bcl-xL, resulting in a drop in mitochondrial membrane transition potential followed by the release of cytochrome c and endonuclease G from mitochondria. However, stimulation of mast cells through Toll-like receptor 4 (TLR4) by lipopolysaccharide prevented mast cell apoptosis by inducing expression of Bcl-xL. Moreover, the activation of mast cells by LPS is enhanced in the presence of IFN-+ , which up-regulates the expression of cell surface TLR4. Taken together, these observations provide evidence that mast cells play important roles not only in allergic reactions but also in innate immunity recognizing enterobacteria through TLR4, and are regulated differently from allergic inflammation by Th1 cytokines.

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Induction of Apoptosis by a Secreted Lipocalin That is Transcriptionally Regulated by IL-3 Deprivation

Cited by 351 publications

References 32 publications

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia

Screening and Identification of Distant Metastasis‐Related Differentially Expressed Genes in Human Squamous Cell Lung Carcinoma

Caspase‐dependent and ‐independent apoptosis of mast cells induced by withdrawal of IL‐3 is prevented by Toll‐like receptor 4‐mediated lipopolysaccharide stimulation

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