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- Title
Activation of cyclin D1-Cdk4 and Cdk4-directed phosphorylation of RB protein in diabetic mesangial hypertrophy.
- Authors
Féliers, Denis; Frank, Meredith A.; Riley, Daniel J.; Féliers, Denis
- Abstract
To determine the role of cell-cycle proteins in regulating pathological renal hypertrophy, diabetes was induced in mice expressing a human retinoblastoma (RB) transgene and in wild-type littermates. Whole-kidney and glomerular hypertrophy caused by hyperglycemia was associated with specific G1 phase cell-cycle events: early and sustained increase in expression of cyclin D1 and activation of cyclin D1-cdk4 complexes, but no change in expression of cyclin E or cdk2 activity. Overexpression of RB alone likewise caused hypertrophy and increased only cyclin D1-cdk4 activity; these effects were not further augmented by high glucose. Identical observations were made when isolated mesangial cells conditionally overexpressing RB from a tetracycline-repressible system hypertrophied in response to high glucose. A mitogenic signal in the same cell-culture system, in contrast, transiently and sequentially activated both cyclin D1-cdk4 and cyclin E-cdk2. In vivo and in cultured mesangial cells, high glucose resulted in persistent partial phosphorylation of RB, an event catalyzed specifically by cyclin D1-cdk4. These data indicate that mesangial hypertrophy caused by hyperglycemia in diabetes results in sustained cyclin D1-cdk4-dependent phosphorylation of RB and maintenance of mesangial cells in the early-to-middle G1 phase of the cell cycle.
- Subjects
PROTEINS; CELL cycle; KIDNEY hypertrophy; DIABETES; RETINOBLASTOMA; PROTEIN metabolism; ANIMAL experimentation; BIOLOGICAL models; CELL culture; COMPARATIVE studies; HYPERTROPHY; TYPE 1 diabetes; KIDNEY glomerulus; RESEARCH methodology; MEDICAL cooperation; MICE; PHOSPHORYLATION; RESEARCH; TRANSFERASES; EVALUATION research
- Publication
Diabetes, 2002, Vol 51, Issue 11, p3290
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.51.11.3290