SND1 Acts Downstream of TGFβ1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis

Yu, Lin; Liu, Xin; Cui, Kang; Di, Yanbo; Xin, Lingbiao; Sun, Xiaoming; Zhang, Wei; Yang, Xi; Wei, Minxin; Yao, Zhi; Yang, Jie

doi:10.1158/0008-5472.can-14-2387

Cited by 82 publications

(76 citation statements)

References 37 publications

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“…SREBP-2 binds to a proximal promoter region containing a serum response element and an enhancer box motif and induces SND1 expression upon cholesterol depletion [16] . Activated Smad2 and Smad3 bind to SND1 promoter and confer TGFβ-medicated induction of SND1 expression [17] [ Figure 1B]. …”

Section: Structure and Activationmentioning

confidence: 99%

“…In higher organisms, repeats of SN domains and the addition of the tudor domain has created a multifunctional protein in SND1 especially with its ability to interact with a diverse array of proteins. SND1 is involved in regulating gene expression by transcriptional activation [18][19][20] , alternative splicing [21] , ubiquitination [17] , mRNA stabilization [22] and RNA interference [23] . These multifaceted properties allow SND1 to positively impact all hallmarks of cancer, notably sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis [24,25] .…”

Section: Multifaceted Propertiesmentioning

confidence: 99%

“…It functions as a co-activator for the transcription factor E2F-1 facilitating G1/S phase transition [28] . SND1 induces the E3 ubiquitin ligase Smurf1 resulting in ubiquitination and degradation of RhoA and promotion of invasion, migration and metastasis [17] . SND1 interacts with the U5 spliceosomal RNA to assemble the spliceosome, affecting the levels of various splice variants, such as generation of a variable form of CD44 that promotes motility and invasiveness of prostate cancer cells [21,29] .…”

Section: Downstream Regulators and Oncogenic Mechanismsmentioning

confidence: 99%

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The multifaceted oncogene SND1 in cancer: focus on hepatocellular carcinoma

Chidambaranathan-Reghupaty

Mendoza

Fisher

et al. 2018

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Staphylococcal nuclease and tudor domain containing 1 (SND1) is a protein that regulates a complex array of functions. It controls gene expression through transcriptional activation, mRNA degradation, mRNA stabilization, ubiquitination and alternative splicing. More than two decades of research has accumulated evidence of the role of SND1 as an oncogene in various cancers. It is a promoter of cancer hallmarks like proliferation, invasion, migration, angiogenesis and metastasis. In addition to these functions, it has a role in lipid metabolism, inflammation and stress response. The participation of SND1 in such varied functions makes it distinct from most oncogenes that are relatively more focused in their role. This becomes important in the case of hepatocellular carcinoma (HCC) since in addition to typical cancer drivers, factors like lipid metabolism deregulation and chronic inflammation can predispose hepatocytes to HCC. The objective of this review is to provide a summary of the current knowledge available on SND1, specifically in relation to HCC and to shed light on its prospect as a therapeutic target.

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Section: Structure and Activationmentioning

confidence: 99%

Section: Multifaceted Propertiesmentioning

confidence: 99%

Section: Downstream Regulators and Oncogenic Mechanismsmentioning

confidence: 99%

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The multifaceted oncogene SND1 in cancer: focus on hepatocellular carcinoma

Chidambaranathan-Reghupaty

Mendoza

Fisher

et al. 2018

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“…It is possible that Smurf-1 is regulated by glucose uptake/metabolism by mechanisms similar to those of Gremlin-1, in which transforming growth factor b-1 (TGFb-1) signaling pathways are amplified (60,62). Indeed, dysregulated TGFb-1 signaling has been documented in pulmonary hypertension (63,64), has opposing effects on BMP signaling (65,66), and can up-regulate the expression of Smurf proteins (67,68). More research is required to determine the links among glucose dysregulation, TGFb-1 signaling, and Smurf-1 expression in IPAH.…”

Section: Original Researchmentioning

confidence: 99%

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Barnes¹,

Kucera²,

Tian³

et al. 2016

Am J Respir Cell Mol Biol

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Altered bone morphogenic protein (BMP) signaling, independent of BMPR2 mutations, can result in idiopathic pulmonary arterial hypertension (IPAH). Glucose dysregulation can regulate multiple processes in IPAH. However, the role of glucose in BMP antagonist expression in IPAH has not been characterized. We hypothesized that glucose uptake regulates BMP signaling through stimulation of BMP antagonist expression in IPAH. Using human plasma, lung tissue, and primary pulmonary arterial smooth muscle cells (PASMCs), we examined the protein expression of BMP2, BMP-regulated Smads, and Smurf-1 in patients with IPAH and control subjects. Gremlin-1 levels were elevated in patients with IPAH compared with control subjects, whereas expression of BMP2 was not different. We demonstrate increased Smad polyubiquitination in IPAH lung tissue and PASMCs that was further enhanced with proteasomal inhibition. Examination of the Smad ubiquitin-ligase, Smurf-1, showed increased protein expression in IPAH lung tissue and localization in the smooth muscle of the pulmonary artery. Glucose dose dependently increased Smurf-1 protein expression in control PASMCs, whereas Smurf-1 in IPAH PASMCs was increased and sustained. Conversely, phosphoSmad1/5/8 levels were reduced in IPAH compared with control PASMCs at physiological glucose concentrations. Interestingly, high glucose concentrations decreased phosphorylation of Smad1/5/8 in control PASMCs. Blocking glucose uptake had opposing effects in IPAH PASMCs, and inhibition of Smurf-1 activity resulted in partial rescue of Smad1/5/8 activation and cell migration rates. Collectively, these data suggest that BMP signaling can be regulated through BMPR2 mutation-independent mechanisms. Gremlin-1 (synonym: induced-in-high-glucose-2 protein) and Smurf-1 may function to inhibit BMP signaling as a consequence of the glucose dysregulation described in IPAH.

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“…The TSN promoter region contains several Smad-specific recognition domains (RD motifs), which were recognized and bound by the Smad complex that enhanced the transcriptional activation of TSN. 74 Since TSN is involved in the regulation of migration and invasion in different cancers its expression level could be used as a potent autonomous poor-prognosis marker.…”

Section: Role Of Tsn In Carcinogenesis and Cell Deathmentioning

confidence: 99%

Tudor staphylococcal nuclease: biochemistry and functions

et al. 2016

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Tudor staphylococcal nuclease (TSN, also known as Tudor-SN, SND1 or p100) is an evolutionarily conserved protein with invariant domain composition, represented by tandem repeat of staphylococcal nuclease domains and a tudor domain. Conservation along significant evolutionary distance, from protozoa to plants and animals, suggests important physiological functions for TSN. It is known that TSN is critically involved in virtually all pathways of gene expression, ranging from transcription to RNA silencing. Owing to its high protein-protein binding affinity coexistent with enzymatic activity, TSN can exert its biochemical function by acting as both a scaffolding molecule of large multiprotein complexes and/or as a nuclease. TSN is indispensible for normal development and stress resistance, whereas its increased expression is closely associated with various types of cancer. Thus, TSN is an attractive target for anti-cancer therapy and a potent tumor marker. Considering ever increasing interest to further understand a multitude of TSN-mediated processes and a mechanistic role of TSN in these processes, here we took an attempt to summarize and update the available information about this intriguing multifunctional protein. TSN is an evolutionarily conserved protein having a pivotal role in the regulation of gene expression. TSN acts both as a scaffolding protein and as a nuclease. TSN sustains cell viability and its cleavage by proteases facilitates cell death. TSN is implicated in key cancer-related processes and is a potent marker of various types of tumors. Open questions:How is nucleolytic activity of TSN regulated in vivo and how this affects interaction of TSN with downstream targets? What are the structural bases and functional consequences of distinct intracellular localization patterns of TSN in animals and plants? What are the molecular mechanisms of the TSN-mediated cancerogenesis?God has given you one face, and you make yourself another (William Shakespeare). Being true for all living organisms, accurate spatio-temporal regulation of gene expression is a fundamental mechanism underlying development, homeostasis and adaptation to the environment. Eukaryotic gene expression is a cumulative outcome of a multitude of molecular processes, including transcription, mRNA splicing, stability and translation, chromatin modification, as well as protein stability and modification. Each of these processes is in turn controlled by a highly dedicated repertoire of proteins. However, one protein, Tudor staphylococcal nuclease (TSN, also known as Tudor-SN, SND1 or p100) appears to act in most of the gene expression pathways.TSN is an evolutionarily conserved protein found in all eukaryotic lineages, except budding yeast, Saccharomyces cerevisiae. Conservation along significant evolutionary distance suggests important physiological functions for TSN. Invariant domain composition of TSN comprises tandem repeat of four staphylococcal nuclease (SN)-like domains (hereafter referred to as SN domains) at the N terminus and a fusio...

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SND1 Acts Downstream of TGFβ1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis

Cited by 82 publications

References 37 publications

The multifaceted oncogene SND1 in cancer: focus on hepatocellular carcinoma

The multifaceted oncogene SND1 in cancer: focus on hepatocellular carcinoma

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Tudor staphylococcal nuclease: biochemistry and functions

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