The Sp transcription factors are involved in the cellular expression of the human glucose-dependent insulinotropic polypeptide receptor gene and overexpressed in adrenals of patients with Cushing’s syndrome

Abstract

The best characterized effect of glucose-dependent insulinotropic polypeptide (GIP) is its stimulatory effect on insulin secretion by pancreatic -cells. Recently, it was demonstrated that some cases of primary adrenal Cushing's syndrome were secondary to the ectopic expression of non-mutated GIP receptor (GIP-R) in bilateral adrenal hyperplasias or unilateral adrenal adenomas, resulting in food-dependent steroidogenesis. Using a human multiple-expression tissue array, GIP-R was found to be expressed in a large number of human adult and fetal tissues, but not in the adrenal gland. The analysis of the promoter region of human (h) GIP-R gene revealed six consensus sequences important in regulating the reporter gene activity and capable of binding to Sp1 and Sp3 transcription factors. Data obtained by gene array and semi-quantitative RT-PCR showed an increase in the expression of Sp3 and CRSP9 (co-regulator of Sp1 transcription factor, subunit 9) in the adrenal adenomas or bilateral macronodular hyperplasias of patients with GIP-dependent Cushing's syndrome; they were, however, also increased in some patients with non-GIP-dependent cortisol-secreting adenomas or with ACTH-dependent Cushing's disease. This study represents the first step in our understanding of the mechanisms involved in the regulation of the expression of the hGIP-R gene.

Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome

“…Moreover, another intriguing point of research in this field is the molecular mechanism responsible for the aberrant expression of G protein-coupled receptors. In this regard, the GIP receptor gene is the most studied, including molecular analysis of its gene promoter (33) and specific transcription factors (34). Such studies and more recently the identification of several target candidate genes (35) are contributing to clarify the causative alterations leading to aberrant expression of hormonal receptors in adrenal cortex.…”

Characterization of the human intestinal CD98 promoter and its regulation by interferon-γ

“…More recently, the Sp1 family has been shown to be involved in inducible gene transcription in response to stimulators such as glucose (3,21), epidermal growth factor (28), and the membrane glycoprotein CD14 (29). Furthermore, increasing evidence suggests that the Sp1 family plays an important regulatory role during proliferation and differentiation (23,26).…”

Multiple aberrant hormone receptors in Cushing's syndrome

“…1) suggesting that GIP can be implicated both in steroidogenesis and cellular proliferation (58). It was suggested that chronic stimulation by ACTH could result in increased GIPR expression (59), but other studies did not confirm GIPR overexpression in the adrenal glands of patients with CD or ectopic ACTH syndrome (58,60,61,62). The demonstration that bovine adrenal cells transfected with the GIP receptor and injected under the renal capsule in mice leads to the development of hyperplastic adrenals and hypercortisolism further supported a role of the ectopic receptor in steroidogenesis and cell proliferation (63).…”