Transforming Growth Factor-β/SMAD Target Gene SKIL Is Negatively Regulated by the Transcriptional Cofactor Complex SNON-SMAD4

Tecalco-Cruz, Ángeles C.; Sosa-Garrocho, Marcela; Vázquez‐Victorio, Genaro; Ortiz-García, Layla; Domínguez‐Hüttinger, Elisa; Macı́as-Silva, Marina

doi:10.1074/jbc.m112.386599

Cited by 40 publications

(36 citation statements)

References 56 publications

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“…This regulation also suggests a time-dependent, negative feedback mechanism on TGF-␤ 1 signaling (58). This has been confirmed in a study by Tecalco-Cruz et al (64) who demonstrated a cluster of functional SBEs within the proximal promoter of the human SnoN gene, which were found to be conserved in the mouse (64). It is curious to note that the Ski gene does not appear to be a direct target of TGF-␤ 1 signaling, which suggests yet another level of complexity to the cellular control of the members of the Ski family of negative TGF-␤ 1 regulators.…”

supporting

confidence: 77%

SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis

Zeglinski

Hnatowich

Jassal

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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supporting

confidence: 77%

SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis

Zeglinski

Hnatowich

Jassal

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…We also found that SOX2 binds the BCL11A locus at multiple sites suggesting a strong direct regulation at the transcriptional level further supporting the data in Figure 3c and d (Figure 3k). BCL11A and SOX2 peaks on SETD8 22,23 , SKIL 24 , TBX2 25 and BCL11A were validated and confirmed by ChIP-qPCR (Supplementary Figure 9). The overlap of the ChIP-Seq peaks suggests a direct interaction between BCL11A and SOX2 proteins, which was confirmed in co-immunoprecipitation experiments on LK2 and H520 (Supplementary Figure 10a, b).…”

Section: Mainmentioning

confidence: 73%

BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma

Lazarus

Hadi

Zambon

et al. 2017

Preprint

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25Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted 26 therapeutic options. We report here the identification and characterisation of the 27 transcriptional regulator, BCL11A, as a LUSC oncogene. Analysis of cancer genomics 28 datasets revealed BCL11A to be upregulated in LUSC but not lung adenocarcinoma 29 (LUAD). We demonstrated that knockdown of BCL11A in LUSC cell lines abolished 30 xenograft tumour growth and its overexpression in vivo led to lung airway hyperplasia 31 and the development of reserve cell hyperplastic lesions. In addition, deletion of Bcl11a 32 in the tracheal basal cells abolished the development of tracheosphere organoids while 33 its overexpression led to solid tracheospheres with a squamous phenotype. At the 34 molecular level we found BCL11A to be a target of SOX2 and we show that it is 35 required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed that 36 BCL11A and SOX2 interact at the protein level and that together they co-regulated the 37 expression of several transcription factors. We demonstrate that pharmacological 38 inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in 39 combination with cisplatin treatment, shows significant selectivity to LUSC in 40 comparison to LUAD cells. Collectively, these results indicate that the disruption of the 41 BCL11A-SOX2 transcriptional program provides a future framework for the 42 development of targeted therapeutic intervention for LUSC patients. 43 44 45 3 Main 46 Lung cancer accounts for the highest rate of cancer related diagnosis and mortality 47 worldwide 1 . Broadly, there are two major types of lung cancer; small cell lung cancer 48 (SCLC) accounting for 15% of the cases and non-small cell lung cancer (NSCLC) 49 accounting for 85% of cases 1 . NSCLC patients have a poor outcome in the clinic with 50 only 15% of patients surviving five years or more 2 . At present NSCLC is defined histo-51 pathologically in the clinic into four broad categories: lung adenocarcinoma (LUAD), 52 lung squamous cell carcinoma (LUSC), large cell carcinoma and undifferentiated non-53 small cell lung cancer. LUAD and LUSC are the most common types of NSCLC (90% 54 of cases). LUSC accounts for more than 400,000 deaths worldwide each year 3 and 55 unlike LUAD there are limited targeted therapies available for LUSC. Platinum-based 56 chemotherapy remains the first-line treatment for LUSC and although the recent FDA 57 approval of Necitumumab in combination with platinum-based chemotherapy for 58 metastatic LUSC has shown positive signs, a great deal of work still needs to be done in 59 this field 4 . 60 61At the cellular level, LUAD tends to originate from the secretory epithelial cells in the 62 lung while LUSC usually originates from basal cells in the main and central airways 2 . 63At the molecular level LUAD is known to harbour mutations in epidermal growth factor 64 receptor (EGFR), V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) 65 and Anaplastic Lymphoma Receptor Tyrosine Kin...

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“…Therefore, there is an adequate theoretical basis to investigate the effects of triptolide on AS. Bone morphogenetic proteins (BMPs) are a family of proteins with multiple biological functions, which can specifically bind to and activate receptors on the membrane of target cells, with small mothers against decapentaplegic (Smad) being the classical pathway of BMP signal transduction (6)(7)(8). The molecular basis and mechanism of control of the BMP/Smad pathway has been investigated extensively, and it has been suggested that AS is treated through this pathway.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of triptolide in treating ankylosing spondylitis through the anti‑ossification effect of the BMP/Smad signaling pathway

et al. 2017

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The present study aimed to examine the mechanism of triptolide in the treatment of ankylosing spondylitis (AS) through the anti‑ossification effect of bone morphogenetic protein (BMP)/small mothers against decapentaplegic (Smad) pathway. Male rats were randomly divided into five groups: Normal rat group; model group; triptolide low dose group (10 mg/kg); triptolide middle dose group (20 mg/kg); triptolide high dose group (40 mg/kg). The spinal joint capsules of each group of rats were collected to perform primary cell culture to determine the levels of cell proliferation. Western blot and reverse transcription‑polymerase chain reaction analyses, and ELISA were used to detect the mRNA and protein expression levels of core‑binding factor α1 (Cbfal), BMP receptor type II (BMPRII), Smad1, Smad4, Smad5 and Smad6, the protein expression of phosphorylation indicators, including phosphorylated (p)Smad1 and pSmad5, the mRNA expression of tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β and IL‑6 in rat plasma, and the mRNA expression of BMP/Smads in fibroblasts induced by recombinant human (rh)BMP‑2. The effects on AS in the rats were also examined. The results revealed that, following intervention with triptolide, inflammation was suppressed, and the mRNA expression levels of TNF‑α, IL‑1β and IL‑6 were reduced. The expression levels of Cbfal, BMPRII, Smad1, Smad4 and Smad5 were also reduced, whereas the expression of Smad6 was increased. Following induction by rhBMP‑2, the effects of triptolide weakened, with the most marked effects observed at the highest concentration, suggesting that triptolide functions through the BMP/Smad signaling pathway. Taken together, the results suggested that triptolide may be used to treat AS, the mechanism of which may be through the BMP/Smad pathway.

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Transforming Growth Factor-β/SMAD Target Gene SKIL Is Negatively Regulated by the Transcriptional Cofactor Complex SNON-SMAD4

Cited by 40 publications

References 56 publications

SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis

SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis

BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma

Mechanism of triptolide in treating ankylosing spondylitis through the anti‑ossification effect of the BMP/Smad signaling pathway

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