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NF-YA overexpression protects from glutamine deprivation.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 5.1 ) Pub Date : 2019-11-09 , DOI: 10.1016/j.bbamcr.2019.118571 Diletta Dolfini 1 , Mario Minuzzo 1 , Sarah Sertic 1 , Roberto Mantovani 1
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 5.1 ) Pub Date : 2019-11-09 , DOI: 10.1016/j.bbamcr.2019.118571 Diletta Dolfini 1 , Mario Minuzzo 1 , Sarah Sertic 1 , Roberto Mantovani 1
Affiliation
The heterotrimeric transcription factor NF-Y binds to CCAAT boxes of genes of glutamine metabolism. We set out to study the role of the regulatory NF-YA subunit in this pathway. We produced U2OS and A549 clones stably overexpressing -OE- the two splicing isoforms of NF-YA. NF-YA OE cells show normal growth and colony formation rates, but they become resistant to cell death upon glutamine deprivation. Increased mRNA and protein expression of the key biosynthetic enzyme GLUL in U2OS entails increased production of endogenous glutamine upon deprivation. The use of GLUL inhibitors dampens the NF-YA-mediated effect. NF-YA OE prevents activation of the pro-apoptotic transcription factor CHOP/DDIT3. Elevated basal levels of SERCA1/2, coding for the molecular target of Thapsigargin, correlate with resistance of NF-YA OE cells to the drug. The work represents a proof-of-principle that elevated levels of NF-YA, as found in some tumor types, helps altering cancer metabolic pathways.
中文翻译:
NF-YA过表达保护免受谷氨酰胺剥夺。
异源三聚体转录因子NF-Y与谷氨酰胺代谢基因的CCAAT盒结合。我们着手研究调节性NF-YA亚基在该途径中的作用。我们产生了稳定过表达-OE- NF-YA的两个剪接亚型的U2OS和A549克隆。NF-YA OE细胞表现出正常的生长和集落形成速率,但在谷氨酰胺剥夺后对细胞死亡具有抵抗力。U2OS中关键生物合成酶GLUL的mRNA和蛋白表达增加,剥夺后内源性谷氨酰胺产生增加。GLUL抑制剂的使用减弱了NF-YA介导的作用。NF-YA OE阻止凋亡前转录因子CHOP / DDIT3的激活。编码Thapsigargin分子靶标的SERCA1 / 2的基础水平升高与NF-YA OE细胞对该药物的耐药性相关。
更新日期:2019-11-11
中文翻译:
NF-YA过表达保护免受谷氨酰胺剥夺。
异源三聚体转录因子NF-Y与谷氨酰胺代谢基因的CCAAT盒结合。我们着手研究调节性NF-YA亚基在该途径中的作用。我们产生了稳定过表达-OE- NF-YA的两个剪接亚型的U2OS和A549克隆。NF-YA OE细胞表现出正常的生长和集落形成速率,但在谷氨酰胺剥夺后对细胞死亡具有抵抗力。U2OS中关键生物合成酶GLUL的mRNA和蛋白表达增加,剥夺后内源性谷氨酰胺产生增加。GLUL抑制剂的使用减弱了NF-YA介导的作用。NF-YA OE阻止凋亡前转录因子CHOP / DDIT3的激活。编码Thapsigargin分子靶标的SERCA1 / 2的基础水平升高与NF-YA OE细胞对该药物的耐药性相关。