The tumor suppressor activity of SOCS-1

Rottapel, Robert; Ilangumaran, Subburaj; Neale, Christopher Andrew; Rose, José La; Ho, Jenny; Nguyen, Melody H.-H.; Barber, Dwayne L.; Dubreuil, Patrice; Sepulveda, Paulo De

doi:10.1038/sj.onc.1205537

Cited by 117 publications

(104 citation statements)

References 52 publications

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“…Downregulation of SOCS-1 by gene promoter hypermethylation has been recently reported in 65% of HCC cell line, 62.9% of multiple myeloma patients samples and 31.6% of pancreatic cancer cell lines with resultant activation of STAT3 (Yoshikawa et al, 2001;Fukushima et al, 2003;Galm et al, 2003). Moreover, restoration of SOCS-1 suppresses tumour growth in HCC and haematopoietic malignancy (Frantsve et al, 2001;Yoshikawa et al, 2001;Rottapel et al, 2002). In this study, we have found that IL-6 was endogenously expressed in several gastric cancer cell lines.…”

Section: Discussionsupporting

confidence: 52%

“…Suppressor of cytokine signalling-1 is downregulated by methylation of the CpG island in human hepatocellular carcinoma (HCC), multiple myeloma and pancreatic ductal neoplasm (Yoshikawa et al, 2001;Nagai et al, 2002;Fukushima et al, 2003;Galm et al, 2003;Okochi et al, 2003). On the other hand, restoration of SOCS-1 suppressed growth in HCC cell lines and oncogene-activated haematopoietic cells (Yoshikawa et al, 2001;Rottapel et al, 2002). Taken together, these data suggest that SOCS-1 functions as a tumour suppressor in the JAK/STAT pathway.…”

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confidence: 75%

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Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

Chan

Leung

et al. 2004

Br J Cancer

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The interleukin-mediated Janus kinase (JAK)/STAT pathway plays a crucial role in carcinogenesis. Recently, increased STAT3 activity was found in hepatocellular carcinoma and multiple myeloma in which there was silencing of SOCS-1 (suppressor of cytokine signalling-1) by gene promoter hypermethylation. We investigated the expression level of interleukin-6 (IL-6) and SOCS-1 in gastric cancer cell lines. Expression of SOCS-1 correlated with IL-6 level in most of the cell lines, except for AGS cells in which SOCS-1 was absent despite a high level of IL-6 production. Methylation analysis by methylation-specific polymerase chain reaction and bisulphite sequencing revealed that CpG island of SOCS-1 was densely methylated in AGS cells. Demethylation treatment by 5 0 azadeoxycytidine restored SOCS-1 expression and also suppressed constitutive STAT3 phosphorylation in AGS cells. Moreover, methylation of SOCS-1 was detected in 27.5% (11 of 40) of primary gastric tumours samples, 10% (one of 10) of adjacent noncancer tissues but not in any (zero of nine) normal gastric mucosa. Methylation of SOCS-1 also correlated with the loss of mRNA expression in some primary gastric cancers. In conclusion, this is the first report to demonstrate that hypermethylation of SOCS-1 led to gene silencing in gastric cancer cell line and primary tumour samples. Downregulation of SOCS-1 cooperates with IL-6 in the activation of JAK/STAT pathway in gastric cancer.

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Section: Discussionsupporting

confidence: 52%

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confidence: 75%

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

Chan

Leung

et al. 2004

Br J Cancer

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“…SOCS1 was found to be directly associated with activated KIT but its inhibitory role in KIT signaling was independent of this interaction in Ba/F3 cells [27] indicating that an alternative mechanism is involved in regulation of receptor signaling by SOCS1. One possibility is that SOCS1 limits the availability of downstream signaling proteins either through ubiquitin-mediated degradation or by competing for the same binding site in the receptor.…”

Section: Socs1mentioning

confidence: 96%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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SOCS proteins in regulation of receptor tyrosine kinase signaling.Uddin, Kazi; Kabir, Nuzhat N; Flores-Morales, Amilcar; Rönnstrand, Lars Link to publication Citation for published version (APA): Kazi, J. U., Kabir, N. N., Flores-Morales, A., & Rönnstrand, L. (2014). SOCS proteins in regulation of receptor tyrosine kinase signaling. Cellular and Molecular Life Sciences, 71(17), 3297-3310. DOI: 10.1007/s00018-014-1619-y General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractThe receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many of this family of kinases are overexpressed or mutated in human malignancies and thus became attractive drug target for cancer treatment. The signaling mediated by RTKs must be tightly regulated by interacting proteins including protein-tyrosine phosphatases and ubiquitin ligases. The suppressor of cytokine signaling (SOCS) family proteins are well known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7 and CIS. A key feature of this family of proteins is the presence of an SH2 domain and a SOCS box. Recent studies suggest that SOCS proteins also play a role in RTK signaling. Activation of RTK results in transcriptional activation of SOCS encoding genes. These proteins associate with RTKs through their SH2 domains and subsequently recruit the E3 ubiquitin machinery through the SOCS box, and thereby limit receptor stability by inducing ubiquitination. In a similar fashion SOCS proteins negatively regulate mitogenic signaling by RTKs. It is also evident that RTKs sometimes can bypass SOCS regulation and SOCS proteins can even potentiate RTKs-mediated mitogenic signaling. Thus apart from negative regulation of receptor signaling, SOCS proteins may also influence signaling in other ways.

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“…Recently, frequent aberrant methylation of the CpG island of SOCS-1 gene in hepatocellular carcinoma (HCC) and in multiple myeloma, and it was also demonstrated that the aberrant methylation had growth suppression activity (Yoshikawa et al, 2001;Galm et al, 2002). These results implicate the JAK/STAT pathway as having growth-promoting properties and suggest that SOCS-1 may normally suppress growth (Bromberg et al, 1999;Rottapel et al, 2002).…”

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confidence: 99%

Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms

et al. 2003

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The suppressor of cytokine signalling-1 (SOCS-1) gene is frequently silenced in human hepatocellular carcinoma by aberrant methylation. The aim of this study was to determine if SOCS-1 is inactivated in pancreatic ductal neoplasms, and to investigate if aberrant methylation of this gene affected the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Aberrant methylation in the CpG island of the SOCS-1 gene was detected in six of 19 (31.6%) human pancreatic cancer cell lines using methylation-specific PCR, and was associated with a loss or reduction of gene expression in five of the six methylated cell lines. Thirteen of 60 pancreatic ductal adenocarcinomas (21.7%) and two of 34 intraductal papillary mucinous neoplasms (IPMNs) (5.9%) had methylated SOCS-1. In contrast, SOCS-1 methylation was not seen in pancreatic normal ductal epithelia (zero out of 15), in pancreatic intraepithelial neoplasia (PanINs) (zero out of 49) or in the IPMNs without infiltrating cancer (zero out of 20). 5-Aza-2 0 -deoxycytidine treatment of the SOCS-1-methylated pancreatic cancer cell lines led to restoration of SOCS-1 gene expression. Interleukin-6, which has been shown to act through the JAK/STAT pathway to increase cell growth, induced modest time and dosedependent cell proliferation in a SOCS-1-methylated cell line (PL10, P ¼ 0.015) but not in two unmethylated cell lines. These results indicate that loss of SOCS-1 gene is associated with transcriptional silencing and may have growth-promoting effects, and that its methylation is a useful marker of pancreatic cancer.

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The tumor suppressor activity of SOCS-1

Cited by 117 publications

References 52 publications

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

SOCS proteins in regulation of receptor tyrosine kinase signaling

Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms

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