Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Sirt1, p53 and p38MAPK are crucial regulators of detrimental phenotypes of ESCs with Max expression ablation

ABSTRACT: Ablation of expression of the Max gene encoding a Myc protein partner in ES cells provoked two major phenomena, i.e. loss of pluripotency and apoptotic cell death. We found that nicotinamide (Nam) significantly alleviates these Max expression ablation-coupled phenotypes in ES cells. To see the alleviation effect of Nam on the overall expression profile of Max-null ES cells whose Max expression is controlled by the tet-off system, we eliminated Max expression by adding doxycycline (Dox) in the presence of Nam. DNA microarray analyses were performed using total RNAs from Nam (4 mM)-treated Max-null ES cells that were cultured in the presence or absence of doxycycline for 6 days.

ORGANISM(S): Mus musculus

SUBMITTER: Akihiko Okuda

PROVIDER: E-GEOD-37917 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Sirt1, p53, and p38(MAPK) are crucial regulators of detrimental phenotypes of embryonic stem cells with Max expression ablation.

Hishida Tomoaki T Nozaki Yuriko Y Nakachi Yutaka Y Mizuno Yosuke Y Iseki Hiroyoshi H Katano Miyuki M Kamon Masayoshi M Hirasaki Masataka M Nishimoto Masazumi M Okazaki Yasushi Y Okuda Akihiko A

Stem cells (Dayton, Ohio) 20120801 8

c-Myc participates in diverse cellular processes including cell cycle control, tumorigenic transformation, and reprogramming of somatic cells to induced pluripotent cells. c-Myc is also an important regulator of self-renewal and pluripotency of embryonic stem cells (ESCs). We recently demonstrated that loss of the Max gene, encoding the best characterized partner for all Myc family proteins, causes loss of the pluripotent state and extensive cell death in ESCs strictly in this order. However, th ...[more]

PMID: 22696478

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Project description:Subinhibitory concentrations of the neuroleptic drug thioridazine (TDZ) are well-known to enhance the killing of methicillin-resistant S. aureus (MRSA) by Î²-lactam antibiotics, however, the mechanism underlying the synergy between TDZ and Î²-lactams is not fully understood. In the present study we have examined the effect of a subinhibitory concentration of TDZ on antimicrobial resistance, the global transcriptome, and the cell wall composition of MRSA USA300. We show that TDZ is able to sensitize the bacteria to several classes of antimicrobials targeting the late stages of peptidoglycan synthesis. Furthermore, our microarray analysis demonstrates that TDZ modulates the expression of genes encoding membrane and surface proteins, transporters, and enzymes involved in amino acid biosynthesis. Interestingly, resemblance between the transcriptional profile of TDZ treatment and the transcriptomic response of S. aureus to known inhibitors of cell wall synthesis suggests that TDZ disturbs peptidoglycan biosynthesis at a stage that precedes transpeptidation. In support of this notion, dramatic changes in the muropeptide profile of USA300 were observed following growth in the presence of TDZ, indicating that TDZ can interfere with the formation of the pentaglycine branches. Strikingly, the addition of glycine to the growth medium relieved the effect of TDZ on the muropeptide profile. Furthermore, exogenous glycine offered a modest protective effect against TDZ-induced Î²-lactam sensitivity. We propose that TDZ exposure leads to a shortage of intracellular amino acids, including glycine, which is required for the production of normal peptidoglycan precursors with pentaglycine branches, the correct substrate of S. aureus penicillin-binding proteins. Collectively, this work demonstrates that TDZ has a major impact on the cell wall biosynthesis pathway in S. aureus and provides new insights into how MRSA may be sensitized towards Î²-lactam antibiotics. Staphylococcus aureus USA300 was grown to early exponential phase and treated with TDZ (16 Âµg/ml) alone or in combination with DCX (0.125 Âµg/ml) for 30 min. Changes in global gene expression were analyzed using the untreated culture as control. Hybridizations were performed in triplicate using RNA isolated from independent cultures.

Dataset Information

Sirt1, p53 and p38MAPK are crucial regulators of detrimental phenotypes of ESCs with Max expression ablation

Publications

Sirt1, p53, and p38(MAPK) are crucial regulators of detrimental phenotypes of embryonic stem cells with Max expression ablation.

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