Neoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain.
Department of Endocrinology, William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Oncogene. 2021 Nov;40(45):6354-6368. doi: 10.1038/s41388-021-02009-8. Epub 2021 Sep 29.
It is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP, result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKCδ resulting in PIT1/CDKN2A-ARF/p53-apoptosis pathway activation. AIP-deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic AIP variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific Aip-knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without AIP mutation abundantly express GDNF, but AIP-mutated tissues have less CDKN2A-ARF expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for AIP-related tumours.
目前尚不清楚广泛表达的共伴侣 AIP 的功能丧失性种系突变如何导致早发性生长激素分泌性垂体肿瘤。RET 受体在生长激素细胞中与 PIT1 独特共表达，在无配体时诱导细胞凋亡，而 RET 与配体结合时支持细胞存活。我们证明，在质膜上，AIP 是与单体细胞内 RET、半胱天冬酶 3 和 PKCδ 形成复合物所必需的，导致 PIT1/CDKN2A-ARF/p53 凋亡途径激活。AIP 缺乏会阻止 RET/caspase-3/PKCδ 的激活，从而阻止 PIT1 的积累和凋亡。RET 诱导的凋亡的抑制作用的存在或缺乏将致病性 AIP 变体与非致病性 AIP 变体区分开来。我们使用新生大鼠病毒基因组学来证明突变 AIP 蛋白对体内 RET 凋亡途径的影响。在成年雄性大鼠中，改变的 AIP 通过阻断 RET 凋亡途径，导致 IGF-1 和巨人症升高，并伴有垂体增生。在雌性中，虽然通过青春期会诱导垂体增生，但 IGF-1 升高和巨人症受到抑制。来自垂体特异性 Aip 敲除小鼠的生长激素腺瘤过度表达 RET 配体 GDNF，从而上调存活途径。患有或不患有 AIP 突变的患者的生长激素腺瘤大量表达 GDNF，但 AIP 突变组织的 CDKN2A-ARF 表达较少。我们的发现解释了 AIP 诱导的生长激素细胞瘤的组织特异性机制，并提供了一个以前未知的致癌机制，为 AIP 相关肿瘤开辟了治疗途径。
