transcriptional stimulation
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BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fang Yu ◽  
Babu Gajendran ◽  
Ning Wang ◽  
Klarke M. Sample ◽  
Wuling Liu ◽  
...  

Abstract Background Cholesterol plays vital roles in human physiology; abnormal levels have deleterious pathological consequences. In cancer, elevated or reduced expression of cholesterol biosynthesis is associated with good or poor prognosis, but the underlying mechanisms are largely unknown. The limonoid compounds A1542 and A1543 stimulate ERK/MAPK by direct binding, leading to leukemic cell death and suppression of leukemia in mouse models. In this study, we investigated the downstream consequences of these ERK/MAPK agonists in leukemic cells. Methods We employed RNAseq analysis combined with Q-RT-PCR, western blot and bioinformatics to identify and confirm genes whose expression was altered by A1542 and A1543 in leukemic cells. ShRNA lentiviruses were used to silence gene expression. Cell culture and an animal model (BALB/c) of erythroleukemia induced by Friend virus were utilized to validate effects of cholesterol on leukemia progression. Results RNAseq analysis of A1542-treated cells revealed the induction of all 18 genes implicated in cholesterol biosynthesis. Expression of these cholesterol genes was blocked by cedrelone, an ERK inhibitor. The cholesterol inhibitor lovastatin diminished ERK/MAPK activation by A1542, thereby reducing leukemic cell death induced by this ERK1/2 agonist. Growth inhibition by cholesterol was observed both at the intracellular level, and when orally administrated into a leukemic mouse model. Both HDL and LDL also suppressed leukemogenesis, implicating these lipids as important prognostic markers for leukemia progression. Mechanistically, knockdown experiments revealed that the activation of SREBP1/2 by A1542-A1543 was responsible for induction of only a sub-set of cholesterol biosynthesis genes. Induction of other regulatory factors by A1542-A1543 including EGR1, AP1 (FOS + JUN) LDLR, IER2 and others may cooperate with SREBP1/2 to induce cholesterol genes. Indeed, pharmacological inhibition of AP1 significantly inhibited cholesterol gene expression induced by A1542. In addition to leukemia, high expression of cholesterol biosynthesis genes was found to correlate with better prognosis in renal cancer. Conclusions This study demonstrates that ERK1/2 agonists suppress leukemia and possibly other types of cancer through transcriptional stimulation of cholesterol biosynthesis genes.


2018 ◽  
Vol 38 (14) ◽  
Author(s):  
Bhawana Uprety ◽  
Amala Kaja ◽  
Sukesh R. Bhaumik

ABSTRACT TOR (target of rapamycin) has been previously implicated in transcriptional stimulation of the ribosomal protein (RP) genes via enhanced recruitment of NuA4 (nucleosome acetyltransferase of H4) to the promoters. However, it is not clearly understood how TOR enhances NuA4 recruitment to the promoters of the RP genes. Here we show that TOR facilitates the recruitment of the 19S proteasome subcomplex to the activator to enhance the targeting of NuA4 to the promoters of the RP genes. NuA4, in turn, promotes the recruitment of TFIID (transcription factor IID, composed of TATA box-binding protein [TBP] and a set of TBP-associated factors [TAFs]) and RNA polymerase II to the promoters of the RP genes to enhance transcriptional initiation. Therefore, our results demonstrate that TOR facilitates the recruitment of the 19S proteasome subcomplex to the promoters of the RP genes to promote the targeting of NuA4 for enhanced preinitiation complex (PIC) formation and consequently transcriptional initiation, hence illuminating TOR regulation of RP gene activation. Further, our results reveal that TOR differentially regulates PIC formation (and hence transcription) at the non-RP genes, thus demonstrating a complex regulation of gene activation by TOR.


2018 ◽  
Vol 69 (6) ◽  
pp. 1415-1432 ◽  
Author(s):  
Elena A Minina ◽  
Panagiotis N Moschou ◽  
Ramesh R Vetukuri ◽  
Victoria Sanchez-Vera ◽  
Catarina Cardoso ◽  
...  

2012 ◽  
Vol 287 (28) ◽  
pp. 23440-23450 ◽  
Author(s):  
Moeko Chujo ◽  
Yusuke Tarumoto ◽  
Koichi Miyatake ◽  
Eisuke Nishida ◽  
Fuyuki Ishikawa

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