Inhibition Of TGF-β Signaling Pathway Research Articles

Design and synthesis of novel thiazole-derivatives as potent ALK5 inhibitors

TGF-β is an immunosuppressive cytokine and plays a key role in progression of cancer by inducing immunosuppression in tumor microenvironment. Therefore, inhibition of TGF-β signaling pathway may provide a potential therapeutic intervention in treating cancers. Herein, we report the discovery of a series of novel thiazole derivatives as potent inhibitors of ALK5, a serine-threonine kinase which is responsible for TGF-β signal transduction. Compound 29b was identified as a potent inhibitor of ALK5 with an IC50 value of 3.7 nM with an excellent kinase selectivity.

P425 Inhibition of TGFβ signaling pathway as a therapeutic approach in collagen VI-related muscular dystrophy

P425 Inhibition of TGFβ signaling pathway as a therapeutic approach in collagen VI-related muscular dystrophy

ASH2L regulates postnatal neurogenesis through Onecut2-mediated inhibition of TGF-β signaling pathway.

The ability of neural stem/progenitor cells (NSPCs) to proliferate and differentiate is required through different stages of neurogenesis. Disturbance in the regulation of neurogenesis causes many neurological diseases, such as intellectual disability, autism, and schizophrenia. However, the intrinsic mechanisms of this regulation in neurogenesis remain poorly understood. Here, we report that Ash2l (Absent, small or homeotic discs-like 2), one core component of a multimeric histone methyltransferase complex, is essential for NSPC fate determination during postnatal neurogenesis. Deletion of Ash2l in NSPCs impairs their capacity for proliferation and differentiation, leading to simplified dendritic arbors in adult-born hippocampal neurons and deficits in cognitive abilities. RNA sequencing data reveal that Ash2l primarily regulates cell fate specification and neuron commitment. Furthermore, we identified Onecut2, a major downstream target of ASH2L characterized by bivalent histone modifications, and demonstrated that constitutive expression of Onecut2 restores defective proliferation and differentiation of NSPCs in adult Ash2l-deficient mice. Importantly, we identified that Onecut2 modulates TGF-β signaling in NSPCs and that treatment with a TGF-β inhibitor rectifies the phenotype of Ash2l-deficient NSPCs. Collectively, our findings reveal the ASH2L-Onecut2-TGF-β signaling axis that mediates postnatal neurogenesis to maintain proper forebrain function.

Krüppel like factor 10 prevents intervertebral disc degeneration via TGF-β signaling pathway both in vitro and in vivo.

BackgroundKrüppel like factor 10 (KLF10), which is also known as TGF-β Inducible Early Gene-1 (TIEG1), plays a crucial role in regulating cell proliferation, cell apoptosis and inflammatory reaction in human carcinoma cells. Moreover, KLF10 knockout in mice leads to severe defects associated with muscle, skeleton and heart etc. However, the function of KLF10 in intervertebral disc degeneration (IVDD) has not been reported yet.MethodsThe relationship between KLF10 and IVDD were investigated in nucleus pulposus (NP) tissues from human and rats. The role of KLF10 in NP cells was explored via loss or gain of function experiments. IVDD rat models were constructed through needle puncture and the effects of KLF10 in IVDD model of rats were investigated via intradiscal injection of KLF10.ResultsWe first found that KLF10 was lowly expressed in degenerative NP tissues and the level of KLF10 showed negative correlation with the disc grades of IVDD patients. Loss or gain of function experiments demonstrated that KLF10 could inhibit apoptosis and enhance migration and proliferation of IL-1β induced NP cells. And KLF10 overexpression reduced extracellular matrix (ECM) degeneration and enhanced ECM synthesis, whereas knockdown of KLF10 resulted in adverse effects. These positive effects of KLF10 could be reversed by the inhibition of TGF-β signaling pathway. In vivo, KLF10 overexpression alleviated IVDD.ConclusionsThis is the first study to reveal that KLF10 was dysregulated in IVDD and overexpressed KLF10 could alleviate IVDD by regulating TGF-β signaling pathway both in vitro and in vivo, which were involved in prohibiting apoptosis, promoting proliferation and migration of NP cells.The translational potential of this article: Overexpression of KLF10 might be an effective therapeutic strategy in the treatment of IVDD.

Resensitization of palbociclib-resistant MCF-7 cells by inhibiting TGF-β-induced epithelial-mesenchymal transition.

e13061 Background: Inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) is the most recent therapeutic method to treat estrogen receptor (ER)-positive breast cancer. Three CDK4/6 inhibitors have been approved by the FDA. The acquired resistance to CDK4/6 inhibitors are expected to have a negative impact on success of breast cancer therapy. It is critical to understand the molecular mechanisms underlying drug resistances to devise a better regimen or overcome drug resistance. Methods: The derivative MCF-7 (MCF-7:PR) cells which exert acquired resistance to palbociclib (PCB), one of the FDA-approved CDK4/6 inhibitors, are recently established. The EMT characteristics, major mechanisms for the EMT, and inhibition of TGF-β signaling pathways are studied in MCF-7:PR cells. Results: The mesenchymal markers are increased and the epithelial ones are decreased at both mRNA and protein levels in our cell line model. Transwell migration and would healing assays also demonstrated that MCF-7:PR cells exert EMT properties. Hyperactivation of TGF-β/Smad signaling was observed in MCF-7:PR cells. Chemical inhibition of TGF-β signaling lead to diminished cell migration and resistance to PCB. Conclusions: Resistance to PCB in MCF-7 cells resulted in significant changes in cell motility and molecular markers associated with EMT. In particular, TGF-β signaling is closely related to EMT and its inhibition reversed the EMT and cellular response to PCT. Our findings suggest that the modulation of EMT via inhibition of TGF-β signaling can be one of strategies to bypass PCB resistance in ER-positive breast cancer.

Therapeutic Targets for the Treatment of Cardiac Fibrosis and Cancer: Focusing on TGF-β Signaling.

Transforming growth factor-β (TGF-β) is a common mediator of cancer progression and fibrosis. Fibrosis can be a significant pathology in multiple organs, including the heart. In this review, we explain how inhibitors of TGF-β signaling can work as antifibrotic therapy. After cardiac injury, profibrotic mediators such as TGF-β, angiotensin II, and endothelin-1 simultaneously activate cardiac fibroblasts, resulting in fibroblast proliferation and migration, deposition of extracellular matrix proteins, and myofibroblast differentiation, which ultimately lead to the development of cardiac fibrosis. The consequences of fibrosis include a wide range of cardiac disorders, including contractile dysfunction, distortion of the cardiac structure, cardiac remodeling, and heart failure. Among various molecular contributors, TGF-β and its signaling pathways which play a major role in carcinogenesis are considered master fibrotic mediators. In fact, recently the inhibition of TGF-β signaling pathways using small molecule inhibitors, antibodies, and gene deletion has shown that the progression of several cancer types was suppressed. Therefore, inhibitors of TGF-β signaling are promising targets for the treatment of tissue fibrosis and cancers. In this review, we discuss the molecular mechanisms of TGF-β in the pathogenesis of cardiac fibrosis and cancer. We will review recent in vitro and in vivo evidence regarding antifibrotic and anticancer actions of TGF-β inhibitors. In addition, we also present available clinical data on therapy based on inhibiting TGF-β signaling for the treatment of cancers and cardiac fibrosis.

MiR-106a-5p modulates apoptosis and metabonomics changes by TGF-β/Smad signaling pathway in cleft palate

BackgroundThe molecular mechanisms of abnormal palatogenesis were investigated in this study. A key regulator, miR-106a-5p, and its target pathway were analyzed. ObjectivesThis research is trying to clarify the underlying mechanism of the modulation of miRNA transcription during the formation of cleft palate by 7T and 9.4T NMR metabolomic platforms. MethodDifferentially expressed miRNAs and mRNAs were analyzed by microarray analysis and verified by qRT-PCR. The protein expression in TGFβ signaling pathways were analyzed by Western Blotting. The relationship between miR-106a-5p and TGFβ were analyzed by luciferase reporter assay. Cell apoptosis were analyzed by flow cytometer. And finally, the metabonomics were analyzed by NMR and multivariate data analysis models (MVDA). ResultsThe expression of miR-106a-5p increased in cleft palatal tissue and negatively correlated with the protein level of Tgfbr2. The luciferase assay further proved that the tgfbr2 was a direct target of miR-106a-5p. In another aspect, miR-106a-5p increased apoptosis level in palatal mesenchymal cells, possibly because its inhibition of TGFβ signaling pathway. Moreover, low cholesterol and choline levels with high citric acid and lipid levels were observed by 7T and 9.4T NMR metabonomic analysis, which inferred the disorder of cell membrane synthesis in cleft palate formation. Furthermore, transformation from choline to phosphatidylcholine regulated by miR-106a-5p was also disrupted, resulting in phosphatidic choline synthesis disorder and reduced cell membrane synthesis. ConclusionsThe regulatory mechanism of cleft palate was studied at transcriptional and metabolomics levels, which may provide important information in understanding the primary cause of this abnormality.

Medium Chain Triglycerides enhances exercise endurance through the increased mitochondrial biogenesis and metabolism.

Medium Chain Triglycerides (MCT) is a dietary supplement and usually used along with medications for treating food absorption disorders including diarrhea, steatorrhea and liver disease. It has been shown that MCT plays a role in lowering weight, and decreasing metabolic syndrome, abdominal obesity and inflammation. However, it is still unknown whether MCT enhances exercise endurance. Here, we demonstrated that MCT containing diet improves high temperature induced exercise performance impairment. We found that MCT up-regulates the expression and protein levels of genes involved in mitochondrial biogenesis and metabolism. Further investigation demonstrated that the increased mitochondrial biogenesis and metabolism is mediated through the activation of Akt and AMPK signaling pathways and inhibition of TGF-β signaling pathway. Collectively, our findings indicate a beneficial effect of dietary MCT in exercise performance through the increase of mitochondrial biogenesis and metabolism.

Dynamic expression and regulatory mechanism of TGF-β signaling in chicken embryonic stem cells differentiating into spermatogonial stem cells.

The present study investigated the dynamic expression and regulatory mechanism of transforming growth factor β (TGF-β) signaling involved in embryonic stem cells (ESCs) differentiation into male germ cells. Candidate genes involved in TGF-β signaling pathway were screened from RNA-sequencing (RNA-seq), which were further validated by quantitative real-time PCR (qRT-PCR). Bone morphogenetic protein 4 (BMP4) was used to induce differentiation of ESCs in vitro. Inhibition of TGF-β signaling pathway was reflected by Western blot of SMAD2 and SMAD5 expression. Differentiating efficiency of germ cells was evaluated by immunofluorescence and fluorescence-activated cell sorting (FACS). Germ cell marker genes were assessed by qRT-PCR in the differentiation process, with activation or inhibition of TGF-β signaling pathway. In the process of in vitro induction, SMAD2 and SMAD5 were found to significantly up-regulated in BMP4 group versus the control and inhibition groups after 4 and 14 days. Expression of CKIT, CVH, DAZL, STRA8, and INTEGRIN α6 were significantly increased in the BMP4 group compared with the control group, while down-regulated in the inhibition groups. The proportion of germ cell-like cells was decreased from 17.9% to 2.2% after 4 days induction, and further decreased from 14.1% to 2.1% after 14 days induction. Correspondingly, expression of marker genes in germ cells was significantly lower. In vivo inhibition of TGF-β signaling pathway reduced germ cells formation from 5.5% to 1.6%, and down-regulated the expression of CKIT, CVH, DAZL, STRA8, and INTEGRIN α6. In conclusion, our study reveals the mechanism regulating spermatogonial stem cells (SSCs) and lays the basis for further understanding of the regulatory network.

Grhl2 reduces invasion and migration through inhibition of TGF\u03b2-induced EMT in gastric cancer

Metastasis is one of the typical features of malignancy that significantly increases cancer-related mortality. Recent studies have shown that epithelial–mesenchymal transition (EMT) is closely related to the invasion and migration of cancer cells. Grainyhead-like 2 (Grhl2), a transcription factor, has been reported to be associated with several tumor processes including EMT. In the previous study, we have reported that Grhl2 functioned as a tumor suppressor in proliferation and apoptosis of gastric cancer. Here we aim to explore the effects of Grhl2 on invasion and migration of gastric cancer and further clarify its possible underlying mechanisms. As a result, in both SGC7901 and MKN45 cells, Grhl2 overexpression significantly inhibited the ability of invasion and migration. In addition, preliminary experiments showed that Grhl2 reduces the protein expression of matrix metalloproteinase-2, -7 and -9 (MMP-2, MMP-7 and MMP-9). Most importantly, Grhl2 antagonizes transforming growth factor-β (TGFβ)-induced EMT, and inhibition of TGFβ signaling pathways can restore Grhl2 expression. Finally, the results of subcutaneous xenograft model indicated that Grhl2 suppresses the growth of gastric cancer and reverses EMT process in vivo. Meanwhile, the metastatic tumor model further confirmed the inhibition of Grhl2 on metastasis of gastric cancer. Taken together, our findings proved that Grhl2, functioned as a tumor suppressor, reduces the invasion and migration through inhibition of TGFβ-induced EMT in gastric cancer.

Is TGFβ as an anti-inflammatory cytokine required for differentiation of inflammatory TH17 cells?

T-Helper 17 (TH17) cells are a CD4+ TH subset that plays a critical role in the pathophysiology of inflammatory disorders, especially chronic forms. It seems that the derivation of TH17 cells from their precursors take place in inflammatory microenvironment. The role of transforming growth factor (TGF)-β as an anti-inflammatory cytokine in TH17 cell differentiation is controversial. To address some of the discrepancies that exist among different studies, this study was undertaken to more clarify the TGFβ role in human TH17 cell differentiation. Here, CD4+ T-cells were isolated from peripheral blood samples and cultured in X-VIVO 15 serum-free medium. Purified cells were then treated with different combinations of polarizing cytokines (interleukin [IL]1-β, -6, and -23, with or without TGFβ), neutralizing anti-interferon (IFN)-γ and anti-IL-4 antibodies and polyclonal stimulators anti-CD3 and -CD28 antibodies, and then analyzed for IL-17, IFNγ, Foxp3, and CD25 expression by flow cytometry and for release of IL-17, -21, -22, and -10 into culture media by ELISA. The effects of selective inhibition of TGFβ signaling pathway on TH17 cell polarization were also determined by using small molecules SB-431542 and A83-01. The current study found that a combination of pro-inflammatory cytokines, including IL-1β, -6, and -23, but not TGFβ, could be used as a cytokine combination to induce development of human TH17 cells. It was also shown that TGFβ acted as a negative regulator in this regard and also led to reduced IL-17 and IL-22 production while inducing Foxp3 expression. Indeed, blocking of TGFβ signaling pathways by selective inhibitors up-regulated TH17 cell differentiation. From the data here, we concluded that TGFβ down-regulates human TH17 cell differentiation and that a presence of pro-inflammatory cytokines (along with IFNγ and IL-4 neutralizing antibodies) is sufficient for optimal differentiation of human TH17 cells.

Abstract 1816: Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells

Abstract The short-chain fatty acid, α-lipoic acid (ALA) is a powerful antioxidant used for treatment of diabetic neuropathy. Recent studies suggested the possibility of ALA as a potential anti-cancer agent, because it could activate adenosine monophosphate activated protein kinase (AMPK) and inhibit transforming growth factor-β (TGFβ) pathway. We evaluate the effects of ALA on thyroid cancer cell proliferation, migration, and invasion. We performed in vitro cell proliferation analysis with BCPAP, HTH-83, CAL-62, and FTC-133 cells. ALA suppressed cell proliferation through activation of AMPK and subsequent down-regulation of mammalian target of rapamycin (mTOR)-S6 signaling pathway. Low-dose ALA, which had minimal effects on cell proliferation, also decreased cell migration and invasion of BCPAP, CAL-62, and HTH-83 cells. ALA inhibited epithelial mesenchymal transition (EMT) evidently by increase of E-cadherin and decreases of activated β-catenin, vimentin, snail, and twist in these cells. ALA suppressed TGFβ production and inhibited induction of p-Smad2, and twist by TGFβ1 or TGFβ2. These findings indicate that ALA reduces thyroid cancer cell migration and invasion through suppression of TGFβ production and inhibition of TGFβ signaling pathways. ALA also significantly suppressed tumor growth in mouse xenograft model using BCPAP and FTC-133 cells. This is the first study to show anti-cancer effect of ALA on thyroid cancer cells. ALA could be a potential therapeutic agent for advanced thyroid cancer, as an adjuvant therapy with other systemic therapeutic agents. Citation Format: Hyemi Kwon, Min Ji Jeon, Won Gu Kim, Seonhee Lim, Soyoung Sim, Tae Yong Kim, Young Kee Shong, Won Bae Kim. Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1816.

Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway.

Interstitial lung disease (ILD) is a serious side-effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Therefore, it is necessary to study underlying mechanisms for the development of pulmonary fibrosis induced by EGFR-TKI and potential approaches to attenuate it. Metformin is a well-established and widely prescribed oral hypoglycemic drug, and has gained attention for its potential anticancer effects. Recent reports have also demonstrated its role in inhibiting epithelial-mesenchymal transition and fibrosis. However, it is unknown whether metformin attenuates EGFR-TKI-induced pulmonary fibrosis. The effect of metformin on EGFR-TKI-induced exacerbation of pulmonary fibrosis was examined in vitro and in vivo using MTT, Ki67 incorporation assay, flow cytometry, immunostaining, Western blot analysis, and a bleomycin-induced pulmonary fibrosis rat model. We found that in lung HFL-1 fibroblast cells, TGF-β or conditioned medium from TKI-treated lung cancer PC-9 cells or conditioned medium from TKI-resistant PC-9GR cells, induced significant fibrosis, as shown by increased expression of Collegen1a1 and α-actin, while metformin inhibited expression of fibrosis markers. Moreover, metformin decreased activation of TGF-β signaling as shown by decreased expression of pSMAD2 and pSMAD3. In vivo, oral administration of gefitinib exacerbated bleomycin-induced pulmonary fibrosis in rats, as demonstrated by HE staining and Masson staining. Significantly, oral co-administration of metformin suppressed exacerbation of bleomycin-induced pulmonary fibrosis by gefitinib. We have shown that metformin attenuates gefitinib-induced exacerbation of TGF-β or bleomycin-induced pulmonary fibrosis. These observations indicate metformin may be combined with EGFR-TKI to treat NSCLC patients.

Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells

The naturally occurring short-chain fatty acid, α-lipoic acid (ALA) is a powerful antioxidant which is clinically used for treatment of diabetic neuropathy. Recent studies suggested the possibility of ALA as a potential anti-cancer agent, because it could activate adenosine monophosphate activated protein kinase (AMPK) and inhibit transforming growth factor-β (TGFβ) pathway. In this study, we evaluate the effects of ALA on thyroid cancer cell proliferation, migration and invasion. We performed in vitro cell proliferation analysis using BCPAP, HTH-83, CAL-62 and FTC-133 cells. ALA suppressed thyroid cancer cell proliferation through activation of AMPK and subsequent down-regulation of mammalian target of rapamycin (mTOR)-S6 signaling pathway. Low-dose ALA, which had minimal effects on cell proliferation, also decreased cell migration and invasion of BCPAP, CAL-62 and HTH-83 cells. ALA inhibited epithelial mesenchymal transition (EMT) evidently by increase of E-cadherin and decreases of activated β-catenin, vimentin, snail, and twist in these cells. ALA suppressed TGFβ production and inhibited induction of p-Smad2 and twist by TGFβ1 or TGFβ2. These findings indicate that ALA reduces cancer cell migration and invasion through suppression of TGFβ production and inhibition of TGFβ signaling pathways in thyroid cancer cells. ALA also significantly suppressed tumor growth in mouse xenograft model using BCPAP and FTC-133 cells. This is the first study to show anti-cancer effect of ALA on thyroid cancer cells. ALA could be a potential therapeutic agent for treatment of advanced thyroid cancer, possibly as an adjuvant therapy with other systemic therapeutic agents.

Inhibition of TGF-β signaling pathway blocks the development of osteosarcoma lung metastases

Inhibition of TGF-β signaling pathway blocks the development of osteosarcoma lung metastases

P2-11-04: TMEPAI Is a Feedback Regulator of TGF-b Signaling during Breast Cancer Progression.

Abstract Background: Despite lack of hormone receptors (ER/PR) and HER2, many triple negative breast cancers (TNBC) depend on transforming growth factor beta (TGF-β) signaling activity for late growth and metastasis. Thus TGF-β signaling is a major potential target to treat TNBC patients. However, inhibition of TGF-β signaling pathway carries the risk of disturbing the tumor suppressive activity of TGF-β in normal tissues and early cancers. Hence, present study was undertaken with a goal to identify suitable markers which will enable to develop drugs that retard only the “oncogenic activity” of TGF-β while preserving its growth suppressive activities. Materials and Methods: All cell lines were cultured according to the recommended standard procedures. Lentiviral mediated expression vector was used to stably knockdown endogenous TMEPAI expression. DNA transfections and luciferase assays were performed according to vendor instructions. Cell proliferation was measured by quantitation of total cellular DNA. Immunoblotting and immunohistochemical analysis were performed using standard methods. Results: Previously we have shown that Transmembrane prostate androgen-induced protein (TMEPAI), a TGF-β inducible gene has the potential to convert tumor suppressive TGF-β into a tumor promoter. In the present study, we show that Smad binding elements driven luciferase reporter activity, a measure of TGF-β signaling, was dramatically increased in TMEPAI knockdown cells. While wild type cancer cells showed transient raise in phosphorylation of Smad2 and Smad3 with TGF-β treatment, TMEPAI knockdown resulted in increased and sustained levels of phosphorylated Smad2 and Smad3. In normal mammary epithelial cells, continuous presence of TGF-β blocked their growth. In contrast, breast cancer cells showed a biphasic growth response (moderate inhibition up to 72h followed by strong growth stimulation) to TGF-β, while TMEPAI-deficiency blocked this response to TGF-β. Furthermore, exogenous expression of TMEPAI in normal mammary epithelial cells and TMEPAI-knockdown cells resulted in reduced TGF-β-dependent Smad activity. Additionally, we found that TMEPAI subverts tumor suppressive TGF-β dependent Smad signaling into tumor promotive non-Smad signaling through stimulation of stress activated protein kinases. Inhibition of stress kinases also reduced the growth of cancer cells similar to TMEPAI deficiency. To evaluate the translational importance of TMEPAI as predictive marker, immunohistochemical analysis on human breast cancer specimens revealed the gain of TMEPAI expressions in aggressive human breast tumor samples but not in normal human breast tissue specimens. Conclusions: Our results show that TMEPAI, which subverts tumor suppressive Smad signaling, may serve as a novel prognostic and predictive marker for aggressive and TGF-β dependent of metastatic breast cancers. These studies will further provide new clues to develop an effective and decisive anti-TGF-β therapy against aggressive breast cancers without disturbing the growth suppression by TGF-β in normal tissues and early tumors. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-04.

B-MYB Positively Regulates Serine-Threonine Kinase Receptor-associated Protein (STRAP) Activity through Direct Interaction

Serine-threonine kinase receptor-associated protein (STRAP) functions as a regulator of both TGF-β and p53 signaling. However, the regulatory mechanism of STRAP activity is not understood. In this study, we report that B-MYB is a new STRAP-interacting protein, and that an amino-terminal DNA-binding domain and an area (amino acids 373-468) between the acidic and conserved regions of B-MYB mediate the B-MYB·STRAP interaction. Functionally, B-MYB enhances STRAP-mediated inhibition of TGF-β signaling pathways, such as apoptosis and growth inhibition, by modulating complex formation between the TGF-β receptor and SMAD3 or SMAD7. Furthermore, coexpression of B-MYB results in a dose-dependent increase in STRAP-mediated stimulation of p53-induced apoptosis and cell cycle arrest via direct interaction. Confocal microscopy showed that B-MYB prevents the normal translocation of SMAD3 in response to TGF-β1 and stimulates p53 nuclear translocation. These results suggest that B-MYB acts as a positive regulator of STRAP.