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核心作用。已在遗传性和散发性内分泌肿瘤中鉴定出导致细胞内 cAMP 增加或直接影响 PKA 亚基表达的遗传异常，但很少见表明存在非基因组病理性 PKA 激活。在本研究中，我们使用分泌人类生长激素 (GH) 的垂体瘤作为显示 PKA-CREB ​​过度激活的内分泌疾病模型，检查了缺氧对 PKA 激活的影响。我们显示缺氧激活 PKA 并增强 CREB ​​转录活性和随后的 GH 过度分泌。这是由于 HIF-1α 具有抑制 PKA 调节亚基 2B ( PRKAR2B)转录的先前未表征的能力。) 通过从PRKAR2B启动子中隔离 Sp1。本研究揭示了一种新机制，转录因子 HIF-1α 通过该机制将环境信号直接转导到 PKA 活性上，而不影响细胞内 cAMP 浓度。通过确定细胞微环境和细胞内酶激活之间的相互作用点，可以更有效地靶向涉及过度激活的 PKA 途径的肿瘤和非肿瘤疾病。