Journal article

Publication year: 2022

Journal: General and Comparative Endocrinology

Volume number: 315

ISSN: 0016-6480

eISSN: 1095-6840

Open access status: Hybrid

DOI Link: https://doi.org/10.1016/j.ygcen.2021.113923

Publisher: Elsevier

Abstract: 
Gonadal function is connected to hypoxia, with hypoxia-inducible factor (HIF) 1 alpha, as a component of HIF1-complexes, regulating cellular adaptation to hypoxic conditions. In the ovary, it regulates follicular maturation, ovulation and luteal development. At the cellular level, HIF1-complexes coordinate the expression of steroidogenic acute regulatory protein (STAR), and thereby ovarian steroidogenesis. The functionality of STAR is associated with the cAMP/PKA-dependent pathways. In vitro, HIF1 alpha is required for basal and cAMP-induced STAR expression, under ambient and reduced oxygen (O-2) tension. Lowering O-2 increases the responsiveness of the Star promoter towards cAMP and PKA mediates activation/phosphorylation (P) of several transcriptional factors, including cJUN and cAMP response element-binding protein (CREB), whose functionality is linked to HIF1 through utilization of CREB-binding protein (CBP). Since the mechanisms underlying HIF1 alpha-dependent expression of STAR remain unknown, we investigated the involvement of HIF1 alpha in CREB-, cJUN- and CBP-mediated expression of STAR using a well-characterized steroidogenic model, murine KK1 granulosa cells; ambient and lowered (10%) O-2 were applied. Our main findings were that while functional suppression of the alpha-subunit of HIF1 lowered STAR/P-STAR and steroidogenic output from granulosa cells, surprisingly the levels of P-CREB and its transcriptional activity were strongly induced. However, its association with the Star promoter was decreased, indicating dissociation of P-CREB from the promoter. Further, suppression of HIF1 activity ultimately diminished the expression of cJUN/P-cJUN and CBP. Finally, the study suggests that HIF1-complex: (1) regulates cJUN expression in granulosa cells, (2) is involved in regulating the recruitment of P-CREB to the Star promoter in (3) a mechanism which possibly involves the HIF1-dependent regulation of CBP expression.

Harvard Citation style: Lanfranchi, B., Rubia, R., Gassmann, M., Schuler, G. and Kowalewski, M. (2022) Transcriptional regulation of HIF1α-mediated STAR expression in murine KK1 granulosa cell line involves cJUN, CREB and CBP-dependent pathways, General and Comparative Endocrinology, 315, Article 113923. https://doi.org/10.1016/j.ygcen.2021.113923

APA Citation style: Lanfranchi, B., Rubia, R., Gassmann, M., Schuler, G., & Kowalewski, M. (2022). Transcriptional regulation of HIF1α-mediated STAR expression in murine KK1 granulosa cell line involves cJUN, CREB and CBP-dependent pathways. General and Comparative Endocrinology. 315, Article 113923. https://doi.org/10.1016/j.ygcen.2021.113923