Regulation of growth hormone biosynthesis by Cdk5 regulatory subunit associated protein 1-like 1 (CDKAL1) in pituitary adenomas

Yoshihiro Takesue, Fan Yan Wei, Hiroyuki Fukuda, Yuki Tanoue, Takahiro Yamamoto, Takeshi Chujo, Naoki Shinojima, Shigetoshi Yano, Motohiro Morioka, Akitake Mukasa, Junichi Kuratsu, Kazuhito Tomizawa

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Abstract

CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) is a tRNA-modifying enzyme that catalyzes 2- methylthiolation (ms2) and has been implicated in the development of type 2 diabetes (T2D). CDKAL1-mediated ms2 is important for efficient protein translation and regulates insulin biosynthesis in pancreatic cells. Interestingly, an association between T2D and release of growth hormone (GH) has been reported in humans. However, it is unknown whether CDKAL1 is important for hormone production in the pituitary gland. The present study investigated the role of CDKAL1 in GHproducing pituitary adenomas (GHPAs). CDKAL1 activity was suppressed in GHPAs, as evidenced by a decrease in ms2, compared with non-functioning pituitary adenomas (NFPAs), which do not produce specific hormones. Downregulation of Cdkal1 using small interfering and short hairpin RNAs increased the biosynthesis and secretion of GH in rat GH3 cells. Depletion of Cdkal1 increased the cytosolic calcium level via downregulation of DnaJ heat shock protein family (Hsp40) member C10 (Dnajc10), which is an endoplasmic reticulum protein related to calcium homeostasis. This stimulated transcription of GH via upregulation of Pit-1. Moreover, CDKAL1 activity was highly sensitive to proteostatic stress and was upregulated by suppression of this stress. Taken together, these results suggest that dysregulation of CDKAL1 is involved in the pathogenesis of GHPAs, and that modulation of the proteostatic stress response might control CDKAL1 activity and facilitate treatment of GHPAs.

Original languageEnglish
Pages (from-to)807-816
Number of pages10
Journalendocrine journal
Volume66
Issue number9
DOIs
Publication statusPublished - 2019 Jan 1
Externally publishedYes

Keywords

  • Growth hormone
  • Hypophyseal tumor
  • Pituitary tumor
  • Protein synthesis
  • Trna

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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    Takesue, Y., Wei, F. Y., Fukuda, H., Tanoue, Y., Yamamoto, T., Chujo, T., Shinojima, N., Yano, S., Morioka, M., Mukasa, A., Kuratsu, J., & Tomizawa, K. (2019). Regulation of growth hormone biosynthesis by Cdk5 regulatory subunit associated protein 1-like 1 (CDKAL1) in pituitary adenomas. endocrine journal, 66(9), 807-816. https://doi.org/10.1507/endocrj.EJ18-0536