Upregulation of p21 activates the intrinsic apoptotic pathway in β-cells.

Angelina M. Hernandez, E. Scott Colvin, Yi Chun Chen, Steven L. Geiss, Lindsay E. Eller, Patrick T. Fueger

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Diabetes manifests from a loss in functional β-cell mass, which is regulated by a dynamic balance of various cellular processes, including β-cell growth, proliferation, and death as well as secretory function. The cell cycle machinery comprised of cyclins, kinases, and inhibitors regulates proliferation. However, their involvement during β-cell stress during the development of diabetes is not well understood. Interestingly, in a screen of multiple cell cycle inhibitors, p21 was dramatically upregulated in INS-1-derived 832/13 cells and rodent islets by two pharmacological inducers of β-cell stress, dexamethasone and thapsigargin. We hypothesized that β-cell stress upregulates p21 to activate the apoptotic pathway and suppress cell survival signaling. To this end, p21 was adenovirally overexpressed in pancreatic rat islets and 832/13 cells. As expected, p21 overexpression resulted in decreased [(3)H]thymidine incorporation. Flow cytometry analysis in p21-transduced 832/13 cells verified lower replication, as indicated by a decreased cell population in the S phase and a block in G2/M transition. The sub-G0 cell population was higher with p21 overexpression and was attributable to apoptosis, as demonstrated by increased annexin-positive stained cells and cleaved caspase-3 protein. p21-mediated caspase-3 cleavage was inhibited by either overexpression of the antiapoptotic mitochondrial protein Bcl-2 or siRNA-mediated suppression of the proapoptotic proteins Bax and Bak. Therefore, an intact intrinsic apoptotic pathway is central for p21-mediated cell death. In summary, our findings indicate that β-cell apoptosis can be triggered by p21 during stress and is thus a potential target to inhibit for protection of functional β-cell mass.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume304
Issue number12
StatePublished - Jun 15 2013
Externally publishedYes

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Up-Regulation
Islets of Langerhans
Caspase 3
Cell Cycle
Cell Death
Apoptosis
Annexins
bcl-2-Associated X Protein
Cyclins
Thapsigargin
Cytoprotection
Mitochondrial Proteins
Helper-Inducer T-Lymphocytes
S Phase
Thymidine
Dexamethasone
Small Interfering RNA
Population
Rodentia
Cell Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hernandez, A. M., Colvin, E. S., Chen, Y. C., Geiss, S. L., Eller, L. E., & Fueger, P. T. (2013). Upregulation of p21 activates the intrinsic apoptotic pathway in β-cells. American Journal of Physiology - Endocrinology and Metabolism, 304(12).

Upregulation of p21 activates the intrinsic apoptotic pathway in β-cells. / Hernandez, Angelina M.; Colvin, E. Scott; Chen, Yi Chun; Geiss, Steven L.; Eller, Lindsay E.; Fueger, Patrick T.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 304, No. 12, 15.06.2013.

Research output: Contribution to journalArticle

Hernandez, AM, Colvin, ES, Chen, YC, Geiss, SL, Eller, LE & Fueger, PT 2013, 'Upregulation of p21 activates the intrinsic apoptotic pathway in β-cells.', American Journal of Physiology - Endocrinology and Metabolism, vol. 304, no. 12.
Hernandez, Angelina M. ; Colvin, E. Scott ; Chen, Yi Chun ; Geiss, Steven L. ; Eller, Lindsay E. ; Fueger, Patrick T. / Upregulation of p21 activates the intrinsic apoptotic pathway in β-cells. In: American Journal of Physiology - Endocrinology and Metabolism. 2013 ; Vol. 304, No. 12.
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