JAGGED1 Expression Is Associated with Prostate Cancer Metastasis and Recurrence

Santagata, Sandro; Demichelis, Francesca; Riva, Alberto; Varambally, Sooryanarayana; Hofer, Matthias; Kutok, Jeffery L.; Kim, Robert; Tang, Jun; Montie, James E.; Chinnaiyan, Arul M.; Rubin, Mark A.; Aster, Jon C.

doi:10.1158/0008-5472.can-04-2500

Cited by 300 publications

(261 citation statements)

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“…10 Jagged-1 is significantly over expressed in metastatic prostate cancer as compared with localized prostate cancer or benign prostatic tissues. 11 Furthermore, high Jagged-1 expression in a subset of clinically localized tumors was significantly associated with recurrence, independent of other clinical parameters. 11 These findings suggest that dysregulation of Jagged-1 protein levels plays a role in prostate cancer cell growth and progression to metastatic disease.…”

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confidence: 93%

“…11 Furthermore, high Jagged-1 expression in a subset of clinically localized tumors was significantly associated with recurrence, independent of other clinical parameters. 11 These findings suggest that dysregulation of Jagged-1 protein levels plays a role in prostate cancer cell growth and progression to metastatic disease. However, the precise role and mechanism of Jagged-1 for prostate cancer cell growth remains unclear.…”

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confidence: 93%

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Retracted: Down‐regulation of Jagged‐1 induces cell growth inhibition and S phase arrest in prostate cancer cells

Zhang

Wang

Ahmed

et al. 2006

Intl Journal of Cancer

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Notch is an ancient cell signaling system that regulates cell fate specification, stem cell maintenance and initiation of differentiation in many tissues. It has been reported that Jagged-1, a Notch ligand, is significantly over expressed in metastatic prostate cancer compared to localized prostate cancer or benign prostatic tissues. Therefore, deregulation of Jagged-1 protein levels may play a role in prostate cancer cell growth and progression. Hence, the aim of our current study was to investigate the mechanistic role of Jagged-1 in prostate cancer cell growth and cell cycle progression. Our results show, for the first time, that down-regulation of Jagged-1 induces cell growth inhibition and S phase cell cycle arrest in prostate cancer cells, with reduced CDK2 kinase activity and increased p27 expression. These results suggest that Jagged-1 could be a potential therapeutic target for the treatment of prostate cancer. ' 2006 Wiley-Liss, Inc.

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confidence: 93%

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confidence: 93%

Retracted: Down‐regulation of Jagged‐1 induces cell growth inhibition and S phase arrest in prostate cancer cells

Zhang

Wang

Ahmed

et al. 2006

Intl Journal of Cancer

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“…Expression level of Jag1 has a positive correlation with the progression of prostate cancer Jagged1 and its coding gene, Jag1, were shown, in many studies, to have a closed correlation with prostate cancer (23)(24)(25)(26)(27)(28), which suggests that Jagged1 functions to promote prostate cancer development. Therefore, we further analyzed Jag1 expressions in prostate cancer tissue samples and normal prostate tissue samples to examine whether Jag1 has a significant higher expression level in advanced prostate cancer.…”

Section: Resultsmentioning

confidence: 99%

“…Jagged1 was found to be highly expressed in most prostate cancer cells and increased in localized prostate cancer compared with benign prostate hyperplasia in the human prostate tumor microarray study (23)(24)(25)(26)(27). Moreover, a positive correlation between Jagged1 and prostate-specific antigen (PSA) recurrence after radical prostatectomy has been found (17), which suggests that high jagged1 protein expression is a strong predictor of prostate cancer recurrence.…”

Section: Introductionmentioning

confidence: 96%

Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged1 in Prostate Cancer by Enhancing Cyclin B1 Expression via Akt Phosphorylation

Yan¹,

Guan

Huang³

et al. 2014

Molecular Cancer Research

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The Jagged1, a Notch signaling pathway ligand, had been shown to have a positive correlation with prostate cancer development. Our study for Jagged1 expression in 218 prostate cancer tissue samples also supports this conclusion. However, the detailed molecular mechanism of Jagged1 in promoting the progression of prostate cancer is still unclear. Through cell proliferation examination, androgen receptor (AR) was found to promote the oncogenic function of Jagged1 to enhance the cell proliferation rate by comparing four prostate cancer cell lines, LNCaP, LAPC4, DU145, and PC3, which was further validated through analyzing the survival of 118 patients treated with androgen-deprivation therapy (ADT) with different expression levels of Jagged1 and AR. More importantly, our data showed that Jagged1 combined with AR could increase the phosphorylation level of Akt and, in turn, phosphorylated Akt plays an important role in regulating the expression level of cyclin B1 by interacting with AR and increasing the transcriptional activity of AR. These data indicate that prostate cancer progression regulated by Jagged1 can be dramatically enhanced by combining with AR through promoting Akt activity.

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“…Specifically, HD domain mutations are found in 40 to 50% of T-ALLs (48), which appear to rely on NOTCH1 signals for growth and survival. Recently, the Notch signaling pathway has been linked to other human cancers, including tumors of the breast (32), brain (35), prostate (41), and pancreas (27), as well as tumor-induced angiogenesis (53). Thus, detailed functional understanding of the mechanisms by which leukemia-associated HD mutations act may also provide insights relevant to other more common forms of human cancer.…”

Section: Discussionmentioning

confidence: 99%

Leukemia-Associated Mutations within the NOTCH1 Heterodimerization Domain Fall into at Least Two Distinct Mechanistic Classes

Malecki

Sanchez-Irizarry

Mitchell

et al. 2006

Molecular and Cellular Biology

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The NOTCH1 receptor is cleaved within its extracellular domain by furin during its maturation, yielding two subunits that are held together noncovalently by a juxtamembrane heterodimerization (HD) domain. Normal NOTCH1 signaling is initiated by the binding of ligand to the extracellular subunit, which renders the transmembrane subunit susceptible to two successive cleavages within and C terminal to the heterodimerization domain, catalyzed by metalloproteases and ␥-secretase, respectively. Because mutations in the heterodimerization domain of NOTCH1 occur frequently in human T-cell acute lymphoblastic leukemia (T-ALL), we assessed the effect of 16 putative tumor-associated mutations on Notch1 signaling and HD domain stability. We show here that 15 of the 16 mutations activate canonical NOTCH1 signaling. Increases in signaling occur in a ligand-independent fashion, require ␥-secretase activity, and correlate with an increased susceptibility to cleavage by metalloproteases. The activating mutations cause soluble NOTCH1 heterodimers to dissociate more readily, either under native conditions (n ‫؍‬ 3) or in the presence of urea (n ‫؍‬ 11). One mutation, an insertion of 14 residues immediately N terminal to the metalloprotease cleavage site, increases metalloprotease sensitivity more than all others, despite a negligible effect on heterodimer stability by comparison, suggesting that the insertion may expose the S2 site by repositioning it relative to protective NOTCH1 ectodomain residues. Together, these studies show that leukemia-associated HD domain mutations render NOTCH1 sensitive to ligand-independent proteolytic activation through two distinct mechanisms.The development of multicellular organisms is orchestrated by a limited number of highly conserved signaling pathways. One such pathway involves NOTCH receptors and downstream mediators, which can variously regulate the specification of cell fate, proliferation, self-renewal, survival, and apoptosis in a dose-and context-dependent fashion (3,47).Like other members of the NOTCH receptor family, mammalian NOTCH1 is a large multimodular type I transmembrane glycoprotein (Fig. 1A). During maturation, NOTCH1 undergoes proteolytic processing by furin at a site termed S1 that lies ϳ70 amino acids external to the transmembrane domain (25), yielding two noncovalently associated extracellular (N EC ) and transmembrane (N TM ) subunits (6,25,37). N EC contains 36 N-terminal epidermal growth factor (EGF)-like repeats that participate in binding to ligands (23, 39, 51) and three iterated LIN-12/NOTCH repeats (LNR), which help to maintain NOTCH receptors in the "off" state prior to ligand binding (13,24,40). The association of N EC and N TM is mediated by sequences lying immediately N terminal (HD-N) and C terminal (HD-C) of site S1; together, these sequences constitute the NOTCH subunit association, or "heterodimerization" (HD) domain (40).Binding of ligands to N EC triggers two sequential proteolytic events within the N TM subunit at sites S2 and S3. S2 cleavage occurs just...

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JAGGED1 Expression Is Associated with Prostate Cancer Metastasis and Recurrence

Cited by 300 publications

References 18 publications

Retracted: Down‐regulation of Jagged‐1 induces cell growth inhibition and S phase arrest in prostate cancer cells

Retracted: Down‐regulation of Jagged‐1 induces cell growth inhibition and S phase arrest in prostate cancer cells

Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged1 in Prostate Cancer by Enhancing Cyclin B1 Expression via Akt Phosphorylation

Leukemia-Associated Mutations within the NOTCH1 Heterodimerization Domain Fall into at Least Two Distinct Mechanistic Classes

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