Differential expression of cell cycle proteins during ageing of pancreatic islet cells.
ABSTRACT One of the major challenges for developmental biologists and investigators in the field of diabetes over the last few decades has been to dissect the origin of pancreatic endocrine cells and to accurately understand the mechanisms that regulate islet cell regeneration. While significant advances have been made recently, there continues to be a paucity of knowledge regarding the growth factor signalling pathways that directly regulate the proteins involved in islet cell cycle control. We will discuss recent work in these areas and provide insights from our studies into age-dependent alterations in the expression of growth factor signalling proteins and cell cycle proteins in islet cells.
Full-textDOI: · Available from: Bernhard Fidelis Maier, Oct 08, 2014
- SourceAvailable from: braintrusters.com[Show abstract] [Hide abstract]
ABSTRACT: Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to metabolic demands. The generation of these adult endocrine cells predominantly occurs through self-replication rather than through differentiation from their stem-cell progenitors; therefore, regulating cellular division through the cell cycle machinery is an essential component of this process. Arrest of the pancreatic β-cell cycle, which abolishes this replication capability, results in an inability to meet the metabolic demand for insulin, disrupting glucose homeostasis collectively driving type 2 diabetes mellitus-the most common metabolic disease worldwide. Therefore, the purpose of this review is to highlight how upstream cell cycle transcriptional regulators, direct cell cycle modulators, and external stress factors such as DNA damage and genomic instability, influence β-cell replication. We specifically highlight and compare recent animal models created to understand β-cell hyperplasia and hypoplasia as well as offer some insight into potential diabetic therapies.Cell cycle (Georgetown, Tex.) 08/2011; 10(15):2471-84. DOI:10.4161/cc.10.15.16741 · 5.01 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Investigating the dynamics of pancreatic β-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that β-cell proliferation and glucose homeostasis were controlled by Δ40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice. We phenotyped metabolic parameters in Δ40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine β-cell proliferation. Transgenic mice with an ectopic p53 gene encoding Δ40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from ∼14 months of age. Consistent with a dramatic decrease in β-cell mass and reduced β-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased. These data indicate a significant and novel role for Δ40p53 in β-cell proliferation with implications for the development of age-dependent diabetes.Diabetes 02/2011; 60(4):1210-22. DOI:10.2337/db09-1379 · 8.47 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Telomerase is a specialized reverse transcriptase that is responsible for extending and preserving the end of the chromosomes (telomeres). Telomerase plays a key role in regulating the lifespan of mammalian cells and is involved in critical aspects of cellular ageing processes. In this review, we will briefly summarize our current understanding of the functions of telomeres, telomerase and their regulation. Considering that compensatory islet hyperplasia and beta-cell regeneration play important roles in the prevention and/or delay of the onset of overt diabetes, we will also examine current literature regarding the effects of diabetes on telomere shortening and provide insights from our own studies on the role of telomerase in beta-cell regeneration.Diabetes Obesity and Metabolism 11/2009; 11 Suppl 4:21-9. DOI:10.1111/j.1463-1326.2009.01103.x · 5.46 Impact Factor