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The pleiotropic regulation of cyclin D1 by newly identified sesaminol-binding protein ANT2
M Watanabe1, Y Iizumi1, M Sukeno1
1Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Abstract:
The expression of cyclin D1 is upregulated in various cancer cells by diverse mechanisms, such as increases in mRNA levels, the promotion of the translation by mammalian target of rapamycin complex 1 (mTORC1) signaling and the protein stabilization. We here show that sesaminol, a sesame lignan, reduces the expression of cyclin D1 with decreasing mRNA expression levels, inhibiting mTORC1 signaling and promoting proteasomal degradation. We subsequently generated sesaminol-immobilized FG beads to newly identify sesaminol-binding proteins. As a consequence, we found that adenine nucleotide translocase 2 (ANT2), the inner mitochondrial membrane protein, directly bound to sesaminol. Consistent with the effects of sesaminol, the depletion of ANT2 caused a reduction in cyclin D1 with decreases in its mRNA levels, mTORC1 inhibition and the proteasomal degradation of its protein, suggesting that sesaminol negatively regulates the function of ANT2. Furthermore, we screened other ANT2-binding compounds and found that the proliferator-activated receptor-γ agonist troglitazone also reduced cyclin D1 expression in a multifaceted manner, analogous to that of the sesaminol treatment and ANT2 depletion. Therefore, the chemical biology approach using magnetic FG beads employed in the present study revealed that sesaminol bound to ANT2, which may pleiotropically upregulate cyclin D1 expression at the mRNA level and protein level with mTORC1 activation and protein stabilization. These results suggest the potential of ANT2 as a target against cyclin D1-overexpressing cancers.
Insights
Sesaminol, a natural compound, reduces cyclin D1 expression by targeting adenine nucleotide translocase 2 (ANT2). This discovery offers a new therapeutic strategy for cancers overexpressing cyclin D1.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Cyclin D1 overexpression is common in various cancers.
- Multiple mechanisms contribute to cyclin D1 upregulation, including mRNA increases, mTORC1 signaling, and protein stabilization.
Purpose of the Study:
- To investigate the mechanism by which sesaminol affects cyclin D1 expression.
- To identify sesaminol-binding proteins and their role in regulating cyclin D1.
Main Methods:
- Sesaminol treatment to assess effects on cyclin D1 expression.
- Generation of sesaminol-immobilized FG beads for protein identification.
- Depletion of identified binding proteins to confirm functional relevance.
- Screening of other compounds targeting identified proteins.
Main Results:
- Sesaminol reduces cyclin D1 by decreasing mRNA, inhibiting mTORC1 signaling, and promoting proteasomal degradation.
- Adenine nucleotide translocase 2 (ANT2) was identified as a direct sesaminol-binding protein.
- ANT2 depletion mimicked sesaminol's effects on cyclin D1, indicating sesaminol targets ANT2.
- Troglitazone, another ANT2-binding compound, also reduced cyclin D1 expression.
Conclusions:
- Sesaminol binds to ANT2, negatively regulating its function and consequently reducing cyclin D1 expression.
- ANT2 plays a key role in pleiotropically upregulating cyclin D1.
- ANT2 represents a potential therapeutic target for cyclin D1-overexpressing cancers.