HACS1 encodes a novel SH3-SAM adaptor protein differentially expressed in normal and malignant hematopoietic cells

Claudio, Jaime O.; Zhu, Yuan Xiao; Benn, Sally J.; Shukla, Anu Heidi; McGlade, C.J.; Falcioni, Nathan; Stewart, A. Keith

doi:10.1038/sj.onc.1204698

Cited by 56 publications

(76 citation statements)

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“…SAMSN1 is mainly expressed by hematopoietic cells and mediates B-cell activation and differentiation. The SAMSN1 gene is located on chromosome 21q11-21, within a region associated with heterozygous deletions that is frequently present in lung cancer cells, suggesting that SAMSN1 acts as a tumor suppressor (13,14). This possibility is supported by (15), which revealed that SAMSN1 is a suppressor of multiple myeloma (15).…”

Section: Introductionsupporting

confidence: 56%

“…SAMSN1 is primarily expressed in human immune tissues as well as in cell lines and primary cells derived from patients with acute myeloid leukemia and multiple myeloma (15,37). In addition, SAMSN1 expression is upregulated by signaling factors that promote the activation and differentiation of B-cells (11,13). The present study hypothesized that chronic inflammation is caused by H. pylori infection-induced dysregulation of immune function and aberrant expression of SAMSN1 (38,39).…”

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confidence: 90%

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Prognostic relevance of SAMSN1 expression in gastric cancer

et al. 2016

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Abstract.The prognosis for patients with advanced gastric cancer (GC) remains poor. The identification of biomarkers relevant to the recurrence and metastasis of GC is advantageous for stratifying patients and proposing novel molecular targets. In the present study the oncological roles of SAM domain, SH3 domain and nuclear localization signals 1 (SAMSN1), a mediator of B-cell function, were elucidated in GC. The expression and methylation status of SAMSN1 were investigated in a panel of 11 GC cell lines. Immunohistochemical staining was performed to determine the pattern of SAMSN1 protein expression in gastric tissues. The prognostic impact of SAMSN1 expression was determined by analyzing 175 pairs of surgically resected gastric tissues. A marked decrease in the level of SAMSN1 mRNA was detected in 8/11 GC cell lines as compared with that in a non-transformed intestinal epithelium cell line (FHs 74) without promoter methylation. The mean expression level of SAMSN1 mRNA was reduced in GC tissues compared with normal adjacent tissues, an observation that was independent of tumor differentiation. The pattern of SAMSN1 protein expression was significantly correlated with that of SAMSN1 mRNA. Low SAMSN1 mRNA expression was significantly associated with tumor size (>60 mm; P=0.026) and shorter overall survival times (P=0.004). Multivariate analysis identified low SAMSN1 mRNA expression as an independent prognostic factor for poor overall survival (hazard ratio, 1.80; 95% confidence interval, 1.07-3.05; P= 0.025). The difference in survival between the low and high SAMSN1 expression groups was more marked in patients with stage II/III GC compared to those with stage IV GC. In patients with stage II/III GC who underwent curative surgery, low SAMSN1 expression was associated with reduced disease free survival times. The results of the present study indicate that downregulation of SAMSN1 transcription may affect the progression and recurrence of GC, and therefore may represent a novel biomarker of GC.

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Section: Introductionsupporting

confidence: 56%

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confidence: 90%

Prognostic relevance of SAMSN1 expression in gastric cancer

et al. 2016

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“…In contrast, the adaptive immune system requires several days to get fully activated and to generate Ag-specific T cells that resolve the infection and provide a long-lasting immunity [10]. SLy1 (SH3-domain protein expressed in Lymphocytes 1) is exclusively expressed in lymphocytes and is part of a family of adapter proteins comprising three members, SLy1 [11], SLy2 [12], and SASH1 (SAM-and SH3-domain containing protein 1) [13]. SLy1 and SLy2 are highly homologous, as both express a bipartite nuclear localization sequence as well as an SH3 and an SAM domain [11,14].…”

Section: Introductionmentioning

confidence: 99%

SLy1 regulates T‐cell proliferation during Listeria monocytogenes infection in a Foxo1‐dependent manner

et al. 2015

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Infection of mice with Listeria monocytogenes results in a strong T-cell response that is critical for an efficient defense. Here, we demonstrate that the adapter protein SLy1 (SH3-domain protein expressed in Lymphocytes 1) is essential for the generation of a fully functional T-cell response. The lack of SLy1 leads to reduced survival rates of infected mice. The increased susceptibility of SLy1 knock-out (KO) mice was caused by reduced proliferation of differentiated T cells. Ex vivo analyses of isolated SLy1 KO T cells displayed a dysregulation of Forkhead box protein O1 shuttling after TCR signaling, whichresulted in an increased expression of cell cycle inhibiting genes, and therefore, reduced expansion of the T-cell population. Forkhead box protein O1 shuttles to the cytoplasm after phosphorylation in a protein complex including 14-3-3 proteins. Interestingly, we observed a similar regulation for the adapter protein SLy1, where TCR stimulation results in SLy1 phosphorylation and SLy1 export to the cytoplasm. Moreover, immunoprecipitation analyses revealed a binding of SLy1 to 14-3-3 proteins. Altogether, this study describes SLy1 as an immunoregulatory protein, which is involved in the generation of adaptive immune responses during L. monocytogenes infection, and provides a model of how SLy1 regulates T-cell proliferation.Keywords: Foxo1 r Infection r Proliferation r SLy1 r T cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionInfection with the intracellular bacterium Listeria monocytogenes (LM) induces strong immune responses, which makes it ideally suited as a model to analyze the innate and adaptive immune responses in mice. Following infection, the innate immune system is quickly activated and serves as a first line defense to control Correspondence: Dr. Sandra Beer-Hammer e-mail: sandra.beer-hammer@uni-tuebingen.de the spreading of the bacteria. Neutrophils, macrophages, and NK cells have been shown to be part of this early response [1][2][3]. The importance of the innate immune system was further demonstrated by a significantly increased susceptibility of mice lacking , , , or IFNR-γ [7], and also by studies with SCID mice that develop chronic listeriosis, but are protected through the innate response from early death [8,9]. In contrast, the adaptive immune system requires several days to get fully activated and to generate Ag-specific T cells that resolve the infection and provide a long-lasting immunity [10].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 3088 Daniel Schäll et al. Eur. J. Immunol. 2015. 45: 3087-3097 SLy1 (SH3-domain protein expressed in Lymphocytes 1) is exclusively expressed in lymphocytes and is part of a family of adapter proteins comprising three members, SLy1 [11], SLy2 [12], and SASH1 (SAM-and SH3-domain containing protein 1) [13]. SLy1 and SLy2 are highly homologous, as both express a bipartite nuclear localization sequence as well as an SH3 and an SAM domain [11,14]. SL...

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“…SLY1 is involved in regulation of the adaptive immune system (Beer et al, 2001(Beer et al, , 2005. HACS1 (or NASH1) is expressed in mast cells, and was reported to be differentially expressed in malignant haematopoietic cells (Claudio et al, 2001;Uchida et al, 2001;Zhu et al, 2004). Whereas the expression of SLY1 and HACS1 seems to be restricted to haematopoietic cells, SASH1 shows ubiquitous expression in human tissue (Zeller et al, 2003).…”

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confidence: 99%

Prognostic significance of downregulated expression of the candidate tumour suppressor gene SASH1 in colon cancer

et al. 2006

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The gene SASH1 (SAM-and SH3-domain containing 1) has originally been identified as a candidate tumour suppressor gene in breast cancer. SASH1 is a member of the SH3-domain containing expressed in lymphocytes (SLY1) gene family that encodes signal adapter proteins composed of several protein -protein interaction domains. The other members of this family are expressed mainly in haematopoietic cells, whereas SASH1 shows ubiquitous expression. We have used quantitative real-time PCR to investigate the expression of SASH1 in tissue samples from 113 patients with colon carcinoma, and compared the expression with 15 normal colon tissue samples. Moreover, nine benign adenomas and 10 liver metastases were analysed. Expression levels of SASH1 were strongly and significantly reduced in colon cancer of UICC stage II, III, and IV, as well as in liver metastases. Moreover, SASH1 was also found to be downregulated on protein levels by immunoblot analysis. However, SASH1 expression was not significantly deregulated in precancerous adenomas and in earlier stage lesions (UICC I). Overall, 48 out of 113 primary colon tumours showed SASH1 expression that was at least 10-fold lower than the levels found in normal colon tissue. Downregulation of SASH1 expression was correlated with the formation of metachronous distant metastasis, and multivariate analysis identified SASH1 downregulation as an independent negative prognostic parameter for patient survival. This study demonstrates for the first time that expression of a member of the SLY1-gene family has prognostic significance in human cancer.

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HACS1 encodes a novel SH3-SAM adaptor protein differentially expressed in normal and malignant hematopoietic cells

Cited by 56 publications

References 18 publications

Prognostic relevance of SAMSN1 expression in gastric cancer

Prognostic relevance of SAMSN1 expression in gastric cancer

SLy1 regulates T‐cell proliferation during Listeria monocytogenes infection in a Foxo1‐dependent manner

Prognostic significance of downregulated expression of the candidate tumour suppressor gene SASH1 in colon cancer

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