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TPD52 inhibits aldosterone synthesis through suppression of CAMKK2 signaling
Ling Xie1, Linqiang Ma1, Bing Kang2
1Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Background:
Aldosterone-producing adenomas (APA) are a major cause of primary aldosteronism. While gene mutations in APA trigger aldosterone overproduction via calcium signaling, their precise regulatory mechanisms remain unclear. Our prior proteomic analysis identified significant upregulation of tumor protein D52 (TPD52), an oncogene protein implicated in cancer progression, in APA. This study investigates the role of TPD52 in regulating aldosterone synthesis and its molecular mechanism.
Methods:
TPD52 expression was validated in APA specimens. Gain- and loss-of-function studies in NCI-H295R cells were performed to assess its role in aldosterone synthesis. Mechanistic insights were obtained through transcriptomics and Co-immunoprecipitation-mass spectrometry (Co-IP-MS), with key results validated in NCI-H295R and HEK-293T cells. Finally, we overexpressed TPD52 in primary APA cells to assess its regulation of aldosterone.
Results:
TPD52 was upregulated in APA tissues. Functionally, TPD52 overexpression suppressed aldosterone synthesis in NCI-H295R cells, whereas its knockdown enhanced aldosterone production. Transcriptomic analysis confirmed that TPD52 knockdown promoted CYP11B2 (aldosterone synthase) expression and aldosterone synthesis. Co-IP-MS identified calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) as a novel TPD52-interacting protein. This interaction suppressed phosphorylation of calmodulin-dependent protein kinase 4 (CAMK4) and CREB. Importantly, CAMKK2 overexpression rescued the TPD52-mediated suppression of CYP11B2 expression and aldosterone synthesis. Overexpression of TPD52 in primary APA cells also reduced CYP11B2 expression and aldosterone production.
Conclusions:
TPD52 acts as a negative regulator of aldosterone synthesis by inhibiting the CAMKK2-CAMK4-CREB signaling axis.
Insights
Tumor protein D52 (TPD52) suppresses aldosterone synthesis in adrenal adenomas by inhibiting the CAMKK2-CAMK4-CREB pathway. This finding clarifies TPD52
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Aldosterone-producing adenomas (APA) cause primary aldosteronism through aldosterone overproduction.
- Gene mutations in APA impact calcium signaling, but regulatory mechanisms are unclear.
- Tumor protein D52 (TPD52), an oncogene, is upregulated in APA and may regulate aldosterone synthesis.
Purpose of the Study:
- To investigate the role of TPD52 in aldosterone synthesis regulation.
- To elucidate the molecular mechanism by which TPD52 affects aldosterone production.
Main Methods:
- TPD52 expression analysis in APA tissues.
- Gain- and loss-of-function studies in NCI-H295R and HEK-293T cell lines.
- Transcriptomic analysis and Co-immunoprecipitation-mass spectrometry (Co-IP-MS) to identify interacting proteins and pathways.
- Overexpression of TPD52 in primary APA cells.
Main Results:
- TPD52 was upregulated in APA tissues.
- TPD52 overexpression suppressed aldosterone synthesis, while knockdown enhanced it.
- TPD52 knockdown increased CYP11B2 (aldosterone synthase) expression.
- TPD52 interacts with CAMKK2, suppressing CAMK4 and CREB phosphorylation.
- CAMKK2 overexpression rescued TPD52-mediated suppression of CYP11B2 and aldosterone synthesis.
Conclusions:
- TPD52 acts as a negative regulator of aldosterone synthesis.
- TPD52 inhibits aldosterone production by suppressing the CAMKK2-CAMK4-CREB signaling axis.
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