Tcf19 is a novel islet factor necessary for proliferation and survival in the INS-1 β-cell line

Kimberly A. Krautkramer, Amelia Linnemann, Danielle A. Fontaine, Amy L. Whillock, Ted W. Harris, Gregory J. Schleis, Nathan A. Truchan, Leilani Marty-Santos, Jeremy A. Lavine, Ondine Cleaver, Michelle E. Kimple, Dawn Belt Davis

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Recently, a novel type 1 diabetes association locus was identified at human chromosome 6p31.3, and transcription factor 19 (TCF19) is a likely causal gene. Little is known about Tcf19, and we now show that it plays a role in both proliferation and apoptosis in insulinoma cells. Tcf19 is expressed in mouse and human islets, with increasing mRNA expression in nondiabetic obesity. The expression of Tcf19 is correlated with β-cell mass expansion, suggesting that it may be a transcriptional regulator of β-cell mass. Increasing proliferation and decreasing apoptotic cell death are two strategies to increase pancreatic β-cell mass and prevent or delay diabetes. siRNA-mediated knockdown of Tcf19 in the INS-1 insulinoma cell line, a β-cell model, results in a decrease in proliferation and an increase in apoptosis. There was a significant reduction in the expression of numerous cell cycle genes from the late G1 phase through the M phase, and cells were arrested at the G1/S checkpoint. We also observed increased apoptosis and susceptibility to endoplasmic reticulum (ER) stress after Tcf19 knockdown. There was a reduction in expression of genes important for the maintenance of ER homeostasis (Bip, p58IPK, Edem1, and calreticulin) and an increase in proapoptotic genes (Bim, Bid, Nix, Gadd34, and Pdia2). Therefore, Tcf19 is necessary for both proliferation and survival and is a novel regulator of these pathways.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume305
Issue number5
DOIs
StatePublished - Sep 17 2013
Externally publishedYes

Fingerprint

Cell Line
Survival
Insulinoma
Apoptosis
Calreticulin
cdc Genes
Endoplasmic Reticulum Stress
G1 Phase
Human Chromosomes
Type 1 Diabetes Mellitus
Endoplasmic Reticulum
Cell Division
Small Interfering RNA
Genes
Homeostasis
Cell Death
Transcription Factors
Obesity
Maintenance
Gene Expression

Keywords

  • β-cell
  • Apoptosis
  • Diabetes
  • Endoplasmic reticulum stress
  • Islet
  • Proliferation
  • Transcription
  • Transcription factor 19

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Tcf19 is a novel islet factor necessary for proliferation and survival in the INS-1 β-cell line. / Krautkramer, Kimberly A.; Linnemann, Amelia; Fontaine, Danielle A.; Whillock, Amy L.; Harris, Ted W.; Schleis, Gregory J.; Truchan, Nathan A.; Marty-Santos, Leilani; Lavine, Jeremy A.; Cleaver, Ondine; Kimple, Michelle E.; Davis, Dawn Belt.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 305, No. 5, 17.09.2013.

Research output: Contribution to journalArticle

Krautkramer, KA, Linnemann, A, Fontaine, DA, Whillock, AL, Harris, TW, Schleis, GJ, Truchan, NA, Marty-Santos, L, Lavine, JA, Cleaver, O, Kimple, ME & Davis, DB 2013, 'Tcf19 is a novel islet factor necessary for proliferation and survival in the INS-1 β-cell line', American Journal of Physiology - Endocrinology and Metabolism, vol. 305, no. 5. https://doi.org/10.1152/ajpendo.00147.2013
Krautkramer, Kimberly A. ; Linnemann, Amelia ; Fontaine, Danielle A. ; Whillock, Amy L. ; Harris, Ted W. ; Schleis, Gregory J. ; Truchan, Nathan A. ; Marty-Santos, Leilani ; Lavine, Jeremy A. ; Cleaver, Ondine ; Kimple, Michelle E. ; Davis, Dawn Belt. / Tcf19 is a novel islet factor necessary for proliferation and survival in the INS-1 β-cell line. In: American Journal of Physiology - Endocrinology and Metabolism. 2013 ; Vol. 305, No. 5.
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abstract = "Recently, a novel type 1 diabetes association locus was identified at human chromosome 6p31.3, and transcription factor 19 (TCF19) is a likely causal gene. Little is known about Tcf19, and we now show that it plays a role in both proliferation and apoptosis in insulinoma cells. Tcf19 is expressed in mouse and human islets, with increasing mRNA expression in nondiabetic obesity. The expression of Tcf19 is correlated with β-cell mass expansion, suggesting that it may be a transcriptional regulator of β-cell mass. Increasing proliferation and decreasing apoptotic cell death are two strategies to increase pancreatic β-cell mass and prevent or delay diabetes. siRNA-mediated knockdown of Tcf19 in the INS-1 insulinoma cell line, a β-cell model, results in a decrease in proliferation and an increase in apoptosis. There was a significant reduction in the expression of numerous cell cycle genes from the late G1 phase through the M phase, and cells were arrested at the G1/S checkpoint. We also observed increased apoptosis and susceptibility to endoplasmic reticulum (ER) stress after Tcf19 knockdown. There was a reduction in expression of genes important for the maintenance of ER homeostasis (Bip, p58IPK, Edem1, and calreticulin) and an increase in proapoptotic genes (Bim, Bid, Nix, Gadd34, and Pdia2). Therefore, Tcf19 is necessary for both proliferation and survival and is a novel regulator of these pathways.",
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AU - Whillock, Amy L.

AU - Harris, Ted W.

AU - Schleis, Gregory J.

AU - Truchan, Nathan A.

AU - Marty-Santos, Leilani

AU - Lavine, Jeremy A.

AU - Cleaver, Ondine

AU - Kimple, Michelle E.

AU - Davis, Dawn Belt

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