CDC6 expression is regulated by lineage-specific transcription factor GATA1

Pavón, Leticia; Calés, Carmela

doi:10.4161/cc.21471

Cited by 10 publications

(11 citation statements)

References 45 publications

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“…B). The mechanism underlying the transcriptional activation of the Cdc6 gene triggered by Tβ 4 knockdown in IEC‐6 cells is unclear even though transcription factors such as GATA‐1 and MyoD have been reported to stimulate Cdc6 expression under certain circumstances (Zhang et al, ;Fernández‐Morales et al, ).…”

Section: Discussionmentioning

confidence: 99%

Thymosin Beta-4 Knockdown in IEC-6 Normal Intestinal Epithelial Cells Induces DNA Re-replication Via Downregulating Emi1

Chao

Chen²,

Tang

et al. 2014

J. Cell. Physiol

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Thymosin β4 (Tβ4 ) is a multifunctional protein already used clinically to treat various diseases; however, the promoting effect of this protein on tumor malignancy should not be neglected. Here, we assessed whether Tβ4 alteration influences normal intestinal epithelial cells because Tβ4 is deemed a novel target for treating colorectal cancer (CRC). For this purpose, we examined the consequences of shRNA-mediated knockdown of Tβ4 in IEC-6 normal rat small intestinal cells and found that inhibiting Tβ4 expression significantly suppressed their growth and induced apoptosis in some cells. Flow cytometric analysis further revealed a marked decrease of G0/G1 population but a drastic increase of polyploid ones in these cells. The increase of polyploidy likely resulted from DNA re-replication because not only the de novo DNA synthesis was greatly increased but also the expression levels of Cdc6 (a replication-licensing factor), cyclin A, and phosphorylated-checkpoint kinase 1 were all dramatically elevated. Moreover, marked reductions in both RNA and protein levels of Emi1 (early mitotic inhibitor 1) were also detected in Tβ4 -downregulated IEC-6 cells which might be accounted by the downregulation of E2F1, a transcription factor capable of inducing Emi1 expression, mediated by glycogen synthase-3β (GSK-3β). To our best knowledge, this is the first report showing that inhibiting Tβ4 expression triggers DNA re-replication in normal intestinal epithelial cells, suggesting that this G-actin sequester may play a crucial role in maintaining genome stability in these cells. More importantly, clinical oncologists should take this novel activity into consideration when design CRC therapy based on targeting Tβ4 .

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Section: Discussionmentioning

confidence: 99%

Thymosin Beta-4 Knockdown in IEC-6 Normal Intestinal Epithelial Cells Induces DNA Re-replication Via Downregulating Emi1

Chao

Chen²,

Tang

et al. 2014

J. Cell. Physiol

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“…[43][44][45][46][47] Cytological changes and modulation of surface receptor expression distinguish each step, making these features suitable markers for every stage of maturation. [48][49][50] In recent years, scientific progress has led to the production of functional platelets in vitro, in order to overcome problems related to platelet transfusion. However, large-scale production for clinical use is far from being achieved, because the number of platelets obtained in vitro is much lower than that in vivo, and manufactured platelets appear activated in the absence of agonists.…”

Section: Discussionmentioning

confidence: 99%

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

et al. 2014

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Platelets modulate vascular system integrity, and their loss is critical in haematological pathologies and after chemotherapy. Therefore, identification of molecules enhancing platelet production would be useful to counteract thrombocytopenia. We have previously shown that 2-arachidonoylglycerol (2-AG) acts as a true agonist of platelets, as well as it commits erythroid precursors toward the megakaryocytic lineage. Against this background, we sought to further interrogate the role of 2-AG in megakaryocyte/platelet physiology by investigating terminal differentiation, and subsequent thrombopoiesis. To this end, we used MEG-01 cells, a human megakaryoblastic cell line able to produce in vitro platelet-like particles.2-AG increased the number of cells showing ruffled surface and enhanced surface expression of specific megakaryocyte/platelet surface antigens, typical hallmarks of terminal megakaryocytic differentiation and platelet production. Changes in cytoskeleton modeling also occurred in differentiated megakaryocytes and blebbing platelets. 2-AG acted by binding to CB 1 and CB 2 receptors, because specific antagonists reverted its effect. Platelets were split off from megakaryocytes and were functional: they contained the platelet-specific surface markers CD61 and CD49, whose levels increased following stimulation with a natural agonist like collagen. Given the importance of 2-AG for driving megakaryopoiesis and thrombopoiesis, not surprisingly we found that its hydrolytic enzymes were tightly controlled by classical inducers of megakaryocyte differentiation.In conclusion 2-AG, by triggering megakaryocyte maturation and platelet release, may have clinical efficacy to counteract thrombocytopenia-related diseases.

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“…; Fernandez‐Morales et al . ). The adjacent localization of GATA and CP2 binding sites is found in the regulatory regions of several other erythroid genes.…”

Section: Discussionmentioning

confidence: 97%

“…; Fernandez‐Morales et al . ). The sequences of these three promoter‐proximal elements are highly conserved between mice and humans (Ohneda et al .…”

Section: Introductionmentioning

confidence: 97%

Verification of the in vivo activity of three distinct cis‐acting elements within the Gata1 gene promoter‐proximal enhancer in mice

et al. 2013

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The transcription factor GATA1 is essential for erythroid and megakaryocytic cell differentiation. Gata1 hematopoietic regulatory domain (G1HRD) has been shown to recapitulate endogenous Gata1 gene expression in transgenic mouse assays in vivo. G1HRD contains a promoter-proximal enhancer composed of a GATA-palindrome motif, four CP2-binding sites and two CACCC boxes. We prepared transgenic reporter mouse lines in which green fluorescent protein and b-galactosidase expression are driven by wild-type G1HRD (as a positive control) and the G1HRD harboring mutations within these cis-acting elements (as the experimental conditions), respectively. Exploiting this transgenic dual reporter (TDR) assay, we show here that in definitive erythropoiesis, G1HRD activity was markedly affected by individual mutations in the GATA-palindrome motif and the CACCC boxes. Mutation of CP2-binding sites also moderately decreased G1HRD activity. The combined mutation of the CP2-binding sites and the GATA-palindrome motif resulted in complete loss of G1HRD activity. In contrast, in primitive erythroid cells, individual mutations of each element did not affect G1HRD activity; G1HRD activity was abolished only when these three mutations were combined. These results thus show that all three elements independently and cooperatively contribute to G1HRD activity in vivo in definitive erythropoiesis, although these are contributing redundantly to primitive erythropoiesis.

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CDC6 expression is regulated by lineage-specific transcription factor GATA1

Cited by 10 publications

References 45 publications

Thymosin Beta-4 Knockdown in IEC-6 Normal Intestinal Epithelial Cells Induces DNA Re-replication Via Downregulating Emi1

Thymosin Beta-4 Knockdown in IEC-6 Normal Intestinal Epithelial Cells Induces DNA Re-replication Via Downregulating Emi1

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

Verification of the in vivo activity of three distinct cis‐acting elements within the Gata1 gene promoter‐proximal enhancer in mice

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