Involvement of the Ca2+-responsive transactivator in high glucose-induced β-cell apoptosis

Abstract

The calcium-regulated transcription coactivator, Ca 2C -responsive transactivator (CREST) was expressed in pancreatic b-cells. Moreover, CREST expression became significantly increased in pancreatic islets isolated from hyperglycemic Goto-Kakizaki rats compared with normoglycemic Wistar controls. In addition, culture of b-cells in the presence of high glucose concentrations also increased CREST expression in vitro. To further investigate the role of this transactivator in the regulation of b-cell function, we established a stable b-cell line with inducible CREST expression. Hence, CREST overexpression mimicked the glucotoxic effects on insulin secretion and cell growth in b-cells. Moreover, high glucose-induced apoptosis was aggravated by upregulation of the transactivator but inhibited when CREST expression was partially silenced by siRNA technology. Further investigation found that upregulation of Bax and downregulation of Bcl2 was indeed induced by its expression, especially under high glucose conditions. In addition, as two causing factors leading to b-cell apoptosis under diabetic conditions, endoplasmic reticulum stress and high free fatty acid, mimicked the high glucose effects on CREST upregulation and generation of apoptosis in b-cells, and these effects were specifically offset by the siRNA knockdown of CREST. These results indicated that CREST is implicated in b-cell apoptosis induced by culture in high glucose and hence that CREST may become a potential pharmacological target for the prevention and treatment of type 2 diabetes mellitus.

Protein expression pattern of calcium-responsive transactivator in early postnatal and adult testes

“…Previous study with Northern blot and in situ hybridization analysis has indicated that CREST mRNA is widely expressed in various peripheral organs and tissues including the testis (Aizawa et al 2004); whereas, the expression of CREST at the protein level has only been detected in the brain and pancreas with Western blot and /or immunohistochemistry (Aizawa et al 2004;Men et al 2013). In the present study, we demonstrated for the first time CREST protein expression in the rat and human testis with immunohistochemical staining.…”

“…In addition to expression in the nervous system, CREST mRNA can also be detected in the peripheral organs of the rats, such as the heart, liver, kidney, pancreas and testis (Aizawa et al 2004;Men et al 2013). Direct relation of the increase in expression of CREST in pancreatic β-cells of hyperglycemic rats to high glucose-induced apoptosis suggests multifunction of CREST in non-nervous tissues (Men et al 2013).…”

“…In addition to expression in the nervous system, CREST mRNA can also be detected in the peripheral organs of the rats, such as the heart, liver, kidney, pancreas and testis (Aizawa et al 2004;Men et al 2013). Direct relation of the increase in expression of CREST in pancreatic β-cells of hyperglycemic rats to high glucose-induced apoptosis suggests multifunction of CREST in non-nervous tissues (Men et al 2013). Interestingly, crest mutant mice often develop infertility (Aizawa et al 2004) and a series of proteins interacting with CREST are found closely related to the differentiation and maturation of the spermatogenic epithelial cells (Gye et al 2001;Don and Stelzer 2002;Boussouar et al 2014;Carre et al 2018).…”