Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
Oncogene. 2020 Apr;39(16):3367-3380. doi: 10.1038/s41388-020-1223-6. Epub 2020 Feb 28.
Overactivation of the cAMP signal transduction pathway plays a central role in the pathogenesis of endocrine tumors. Genetic aberrations leading to increased intracellular cAMP or directly affecting PKA subunit expression have been identified in inherited and sporadic endocrine tumors, but are rare indicating the presence of nongenomic pathological PKA activation. In the present study, we examined the impact of hypoxia on PKA activation using human growth hormone (GH)-secreting pituitary tumors as a model of an endocrine disease displaying PKA-CREB overactivation. We show that hypoxia activates PKA and enhances CREB transcriptional activity and subsequently GH oversecretion. This is due to a previously uncharacterized ability of HIF-1α to suppress the transcription of the PKA regulatory subunit 2B (PRKAR2B) by sequestering Sp1 from the PRKAR2B promoter. The present study reveals a novel mechanism through which the transcription factor HIF-1α transduces environmental signals directly onto PKA activity, without affecting intracellular cAMP concentrations. By identifying a point of interaction between the cellular microenvironment and intracellular enzyme activation, neoplastic, and nonneoplastic diseases involving overactivated PKA pathway may be more efficiently targeted.
cAMP 信号转导通路的过度激活在内分泌肿瘤的发病机制中起着核心作用。在遗传性和散发性内分泌肿瘤中已经发现了导致细胞内 cAMP 增加或直接影响 PKA 亚基表达的遗传异常，但这些异常非常罕见，表明存在非基因组病理性 PKA 激活。在本研究中，我们使用生长激素（GH）分泌性垂体肿瘤作为内分泌疾病的模型，检测了缺氧对 PKA 激活的影响，该疾病表现为 PKA-CREB 过度激活。我们发现缺氧激活了 PKA，并增强了 CREB 的转录活性，随后导致 GH 过度分泌。这是由于 HIF-1α 以前未被描述的能力，通过将 Sp1 从 PRKAR2B 启动子上隔离出来，抑制 PKA 调节亚基 2B（PRKAR2B）的转录。本研究揭示了一种新的机制，即转录因子 HIF-1α 可以直接将环境信号转导到 PKA 活性上，而不影响细胞内 cAMP 浓度。通过确定细胞微环境与细胞内酶激活之间的相互作用点，涉及过度激活的 PKA 通路的肿瘤和非肿瘤疾病可能会更有效地被靶向治疗。
