Asynchronous Rhythm of Ad4BP/SF-1 and Per2 Expression in Adrenal Tumors of Cushing’s Syndrome Volume 7 - Issue 1
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2018, Vol 7, Issue 1
Abstract
The relationship between circadian rhythm and autonomous cortisol secretion of adrenocortical lesions associated with Cushing’s syndrome is still unknown. We show here that in Y1 adrenocortical tumor cells, circadian rhythm of Per2 mRNA expression was in a 24 h manner, while that of steroidogenic-related genes such as P450scc mRNA and Ad4BP/SF-1 mRNA was asynchronous with Per 2 mRNA, compared to normal mouse adrenal primary culture tissue which show synchronized expression of the three genes. Deletion mutants of Ad4BP/SF-1 promoter activity in Y1 cells show that the E-box element functioned in a circadian-like pattern which was abrogated in promoter constructs which lack the E-box. Rhythm of upstream factor-1 (USF-1) mRNA correlated with Ad4BP/SF-1 mRNA expression, which is known to bind the E-box of Ad4BP/SF-1 promoter. Finally, we were able to detect asynchronous rhythm of P450scc, Ad4BP/SF-1 compared with Per2 promoter activity in primary cultured cells derived from adrenocortical lesions associated with Cushing’s syndrome. We believe the results presented here a result of tumorigenesis rather than evoking it, but we are certain that the method used here will provide us tools in deciphering the mechanism of tumorigenesis. Thus, we conclude asynchronous expression of Ad4BP/SF-1 and Per2 is in part related to the pathogenesis in adrenocortical lesions of Cushing’s syndrome. The primary adrenal form of Cushing’s syndrome is characterized by ACTH-independent autonomous cortisol secretion from adrenocortical tumors with diminished diurnal rhythm. The normal adrenal gland produces cortisol stimulated by rhythmic secretion of ACTH from the pituitary gland driven by CRH secretion from parvocellular neurons of the paraventricular nucleus of the hypothalamus. Circadian circuits stimulate suprachiasmatic nucleus (SCN) afferents which stimulate CRH secretion [1,2]. In addition to this hypothalamus pituitary adrenal (HPA) axis activity, the peripheral clock of the adrenal gland is known to be activated by light via the suprachiasmatic nucleus-sympathetic nervous system in the absence of ACTH [3]. A continuous loss of rhythmic, but robust and autonomous cortisol secretion from adrenal tumors is ACTH-independent and in some cases ectopic hormone receptors are expressed in the tumors which aberrantly stimulate cortisol secretion [4]. Together with activating mutations of the gene coding for the stimulatory G protein α subunit (GNAS) in adrenocorticotropin independent macronodular adrenocortical hyperplasia (AIMAH) [5] and mutations of protein kinase, Camp dependent, regulatory, type I, α gene (PRKAR1A) in primary pigmented nodular adrenocortical disease (PPNAD), and other accumulating evidence has endorsed the idea that adrenocortical lesions of Cushing’s syndrome harbor abnormalities of the cyclic AMP signaling pathway [6]. An extensively detailed evaluation of cortisol level in patients with adrenocortical lesions of Cushing’s syndrome has found increased pulsatile secretion and delay in phase shift of 3h [7]. This is reminiscent with the Clock mutant mouse where circadian period was 27.3h in constant darkness [8]. It remains unclear whether the autonomous secretion of cortisol by the adrenal tumor is brought by abnormal rhythm of circadian related genes. Per2 is an important component of the circadian clock system and participates in both input and output pathways of the clock [9]. The blunted response to ACTH of steroid secretion in Per2/Cry1 mutant mice has revealed that the adrenal clock gates the sensitivity to ACTH [10]. Though rate-limiting components of steroidogenesis such as P450scc show no transcriptional circadian rhythm [10], a nuclear factor, Ad4BP/ SF-1 is known to respond to light through the suprachiasmatic nucleus-sympathetic nervous system [3]. Since the mechanism of response of Ad4BP/SF-1 activity to cAMP accumulation is still an open question [11] Ad4BP/SF-1 may be involved in the abnormal steroid secretion in adrenocortical lesions of Cushing’s syndrome.
Authors and Affiliations
Kenji Ohe, Tomoko Tanaka, Hiroki Terai, Masayoshi Mori, Yusuke Murata, Munechika Enjoji, Makoto Akashi, Toshihiko Yanase
Keywords
Related Articles
- EP ID EP592694
- DOI 10.26717/BJSTR.2018.07.001459
- Views 147
- Downloads 0
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