CRN2M, Unité Mixte de Recherche 6231, Department of Neuroendocrinology-Neuroimmunology, Institut Fédératif Jean-Roche, Faculté de Médecine Secteur Nord, Université de la Méditerranée CS80011, Boulevard Pierre Dramard, 13344 Marseille cedex 15, France.
Endocrinology. 2011 Apr;152(4):1234-43. doi: 10.1210/en.2010-1077. Epub 2011 Feb 1.
The MAPK ERK1/2 cascade regulates all the critical cellular functions, and in many pathological situations, these regulatory processes are perturbed. It has been clearly established that this cascade is an integrative point in the control of the pituitary functions exerted by various extracellular signals. In particular, ERK1/2 cross talk with the cAMP pathway is determinant in the control of somatolactotroph hormonal secretion exerted via neuropeptide receptors. GH-secreting adenomas are characterized by frequent cAMP pathway alterations, such as constitutive activation of the α-subunit of the heterotrimeric Gs protein (the gsp oncogene), overexpression of Gsα, and changes in the protein kinase A regulatory subunits. However, it has not yet been established exactly how these alterations result in GH-secreting adenomas or how the ERK1/2 cascade contributes to the process of GH-secreting adenoma tumorigenesis. In this study on the conditional gsp-oncogene-expressing GH4C1 cell line, expression of the gsp oncogene, which was observed in up to 40% of GH-secreting adenomas, was found to induce sustained ERK1/2 activation, which required activation of the protein kinase A and the GTPases Ras and Rap1. All these signaling components contribute to the chronic activation of the human prolactin promoter. The data obtained here show that Ras plays a crucial role in these processes: in a physiopathological context, i.e. in the presence of the gsp oncogene, it switched from being a repressor of the cAMP/ protein kinase A ERK-sensitive prolactin gene control exerted by neuropeptides to an activator of the prolactin promoter.
MAPK ERK1/2 级联调节所有关键的细胞功能，在许多病理情况下，这些调节过程会受到干扰。已经明确的是，该级联是各种细胞外信号对垂体功能进行控制的综合点。特别是，ERK1/2 与 cAMP 途径的串扰在通过神经肽受体控制生长激素分泌细胞的激素分泌中起决定作用。生长激素分泌腺瘤的特征是 cAMP 途径经常发生改变，例如异三聚体 Gs 蛋白的α亚基（gsp 癌基因）组成性激活、Gsα的过表达以及蛋白激酶 A 调节亚基的改变。然而，目前尚不清楚这些改变如何导致生长激素分泌腺瘤，或者 ERK1/2 级联如何促进生长激素分泌腺瘤的肿瘤发生过程。在这项关于条件性 gsp 癌基因表达的 GH4C1 细胞系的研究中，观察到高达 40%的生长激素分泌腺瘤中存在 gsp 癌基因的表达，导致持续的 ERK1/2 激活，这需要蛋白激酶 A 和 GTPases Ras 和 Rap1 的激活。所有这些信号成分都有助于慢性激活人催乳素启动子。这里获得的数据表明 Ras 在这些过程中起着至关重要的作用：在生理病理环境中，即在存在 gsp 癌基因的情况下，它从作为神经肽介导的 cAMP/蛋白激酶 A ERK 敏感催乳素基因控制的抑制剂转变为催乳素启动子的激活剂。
