Gene Expression in Mouse Thyrotrope Adenoma: Transcription Elongation Factor Stimulates Proliferation

Endocrinology. 2016 Sep;157(9):3631-46. doi: 10.1210/en.2016-1183. Epub 2016 Jul 19.

Abstract

Thyrotrope hyperplasia and hypertrophy are common responses to primary hypothyroidism. To understand the genetic regulation of these processes, we studied gene expression changes in the pituitaries of Cga(-/-) mice, which are deficient in the common α-subunit of TSH, LH, and FSH. These mice have thyrotrope hypertrophy and hyperplasia and develop thyrotrope adenoma. We report that cell proliferation is increased, but the expression of most stem cell markers is unchanged. The α-subunit is required for secretion of the glycoprotein hormone β-subunits, and mutants exhibit elevated expression of many genes involved in the unfolded protein response, consistent with dilation and stress of the endoplasmic reticulum. Mutants have elevated expression of transcription factors that are important in thyrotrope function, such as Gata2 and Islet 1, and those that stimulate proliferation, including Nupr1, E2f1, and Etv5. We characterized the expression and function of a novel, overexpressed gene, transcription elongation factor A (SII)-like 5 (Tceal5). Stable expression of Tceal5 in a pituitary progenitor cell line is sufficient to increase cell proliferation. Thus, Tceal5 may act as a proto-oncogene. This study provides a rich resource for comparing pituitary transcriptomes and an analysis of gene expression networks.

MeSH terms

  • Adenoma / metabolism*
  • Amino Acid Sequence
  • Animals
  • Cell Proliferation
  • Endoplasmic Reticulum / ultrastructure
  • Endoplasmic Reticulum Stress
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Glycoprotein Hormones, alpha Subunit / genetics
  • Hypothyroidism / metabolism*
  • Male
  • Mice
  • Molecular Sequence Data
  • Pituitary Neoplasms / metabolism*
  • Proto-Oncogene Mas
  • Thyrotrophs / metabolism*
  • Thyrotropin, beta Subunit / metabolism
  • Transcription Factors / metabolism*
  • Transcriptional Elongation Factors / metabolism
  • Unfolded Protein Response

Substances

  • Glycoprotein Hormones, alpha Subunit
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Tceal5 protein, mouse
  • Thyrotropin, beta Subunit
  • Transcription Factors
  • Transcriptional Elongation Factors