TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

Epping, Mirjam T.; Lunardi, Andrea; Nachmani, Daphna; Castillo-Martín, Mireia; Thin, Tin Htwe; Cordon‐Cardo, Carlos; Pandolfi, Pier Paolo

doi:10.1038/cdd.2014.226

Cited by 38 publications

(34 citation statements)

References 40 publications

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“…Moreover, the loss of REST expression in breast cancer significantly correlated with recurrence and poor survival of breast cancer patients. Additionally, the TSPY2/REST complex induces transcriptional repression of TrkC and restores the tumor inhibitory activity of TGF-β [144,145].…”

Section: The Biological Function Of Trkc In Cancermentioning

confidence: 99%

Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer

Jin

2020

Cancers

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Tropomyosin receptor kinase (Trk) C contributes to the clinicopathology of a variety of human cancers, and new chimeric oncoproteins containing the tyrosine kinase domain of TrkC occur after fusion to the partner genes. Overexpression of TrkC and TrkC fusion proteins was observed in patients with a variety of cancers, including mesenchymal, hematopoietic, and those of epithelial cell lineage. Both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) were involved in the regulation of TrkC expression through transcriptional and posttranscriptional alteration. Aberrant activation of TrkC and TrkC fusion proteins markedly induces the epithelial-mesenchymal transition (EMT) program, growth rate, tumorigenic capacity via constitutive activation of Ras-MAP kinase (MAPK), PI3K-AKT, and the JAK2-STAT3 pathway. The clinical trial of TrkC or TrkC fusion-positive cancers with newly developed Trk inhibitors demonstrated that Trk inhibitors were highly effective in inducing tumor regression in patients who do not harbor mutations in the kinase domain. Recently, there has been a progressive accumulation of mutations in TrkC or the TrkC fusion protein detected in the clinic and its related cancer cell lines caused by high-throughput DNA sequencing. Despite given the high overall response rate against Trk or Trk fusion proteins-positive solid tumors, acquired drug resistance was observed in patients with various cancers caused by mutations in the Trk kinase domain. To overcome acquired resistance caused by kinase domain mutation, next-generation Trk inhibitors have been developed, and these inhibitors are currently under investigation in clinical trials.

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Section: The Biological Function Of Trkc In Cancermentioning

confidence: 99%

Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer

Jin

2020

Cancers

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“…In epithelial cells, REST level is high. Its loss is bound to cancer, its recurrence, and poor prognosis [54,55]. Finally, in liver cancer cells, REST level is variable.…”

Section: Cancersmentioning

confidence: 99%

News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology

García-Manteiga

D’Alessandro

Meldolesi

2019

IJMS

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RE-1 silencing transcription factor (REST) (known also as NRSF) is a well-known transcription repressor whose strong decrease induces the distinction of neurons with respect to the other cells. Such distinction depends on the marked increased/decreased expression of specific genes, accompanied by parallel changes of the corresponding proteins. Many properties of REST had been identified in the past. Here we report those identified during the last 5 years. Among physiological discoveries are hundreds of genes governed directly/indirectly by REST, the mechanisms of its neuron/fibroblast conversions, and the cooperations with numerous distinct factors induced at the epigenetic level and essential for REST specific functions. New effects induced in neurons during brain diseases depend on the localization of REST, in the nucleus, where functions and toxicity occur, and in the cytoplasm. The effects of REST, including cell aggression or protection, are variable in neurodegenerative diseases in view of the distinct mechanisms of their pathology. Moreover, cooperations are among the mechanisms that govern the severity of brain cancers, glioblastomas, and medulloblastomas. Interestingly, the role in cancers is relevant also for therapeutic perspectives affecting the REST cooperations. In conclusion, part of the new REST knowledge in physiology and pathology appears promising for future developments in research and brain diseases.

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“…In non-small cell lung cancer cell lines, TGFβ upregulates TSPYL2 expression [13] and TSPYL2 itself enhances TGFβ signaling by interacting with the REST multisubunit transcriptional repressor complex [14]. Moreover, TSPYL2 was found mutated in endometrial carcinoma [15] and downregulated in glioma [16,17].…”

Section: Introductionmentioning

confidence: 99%

TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage

et al. 2018

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Protein acetylation and deacetylation events are finely regulated by lysine-acetyl-transferases and lysine-deacetylases and constitute an important tool for the activation or inhibition of specific cellular pathways. One of the most important lysine-acetyl-transferases is p300, which is involved in the regulation of gene expression, cell growth, DNA repair, differentiation, apoptosis, and tumorigenesis. A well-known target of p300 is constituted by the tumor suppressor protein p53, which plays a critical role in the maintenance of genomic stability and whose activity is known to be controlled by post-translational modifications, among which acetylation. p300 activity toward p53 is negatively regulated by the NAD-dependent deacetylase SIRT1, which deacetylates p53 preventing its transcriptional activation and the induction of p53-dependent apoptosis. However, the mechanisms responsible for p53 regulation by p300 and SIRT1 are still poorly understood. Here we identify the nucleosome assembly protein TSPY-Like 2 (TSPYL2, also known as TSPX, DENTT, and CDA1) as a novel regulator of SIRT1 and p300 function. We demonstrate that, upon DNA damage, TSPYL2 inhibits SIRT1, disrupting its association with target proteins, and promotes p300 acetylation and activation, finally stimulating p53 acetylation and p53-dependent cell death. Indeed, in response to DNA damage, cells silenced for TSPYL2 were found to be defective in p53 activation and apoptosis induction and these events were shown to be dependent on SIRT1 and p300 function. Collectively, our results shed new light on the regulation of p53 acetylation and activation and reveal a novel TSPYL2 function with important implications in cancerogenesis.

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TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

Cited by 38 publications

References 40 publications

Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer

Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer

News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology

TSPYL2 is a novel regulator of SIRT1 and p300 activity in response to DNA damage

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