Figure legend: p38MAPK Controls Expression of Multiple Cell Cycle Inhibitors and Islet
Proliferation with Advancing Age:
(A) Activation of p38MAPK is Required for Induction of Inhibitors of Cyclin-Dependent Kinases with Age. Analysis of genes expression in young (2–3 months old, Y) and old (22–25 months old, O) WT and p38AF/+ mice was carried out in different organs using RT-PCR. At least six mice for each genotype were used for analysis. *p < 0.05
(B) p38MAPK Attenuates Islet Regeneration with Aging. WT and p38AF/+ mice of different age (as indicated in the panel) were treated with STZ and their blood glucose levels determined weekly. All mice that died within 2 weeks following injection were excluded from analysis. Wild-type mice are depicted with a solid and p38AF/+ with a dashed line
(C) p38MAPK Attenuates Islet Proliferation. Islet proliferation was measured by KI67 staining, and was performed on young (2–3 months) and old (22–24 months) wild-type and p38AF/+ mice.
(D) Bmi1 Binding to the Ink4a Promoter Is Regulated in a p38-Dependent Manner with Aging. Analysis of Bmi1 binding to the Ink4a promoter was analyzed by ChIP in splenocytes obtained from young (2–3 months old) and old (22–25 months old) WT and p38AF/+ mice. At least six mice for each genotype were used for analysis. *p < 0.05.
(E) Islet proliferation in Wip1-deficient mice is reduced in a p38MAPK-dependent manner. Analysis of KI67-positive cells in islets of 4- to 6-month-old mice of different genotypes.
(F) Overexpression of Wip1 is sufficient to overcome age-related decline in islet proliferation. Islet proliferation based on KI67 staining was analyzed in young (2–3 months) and aged (11–13 months) WT and UbC-Wip1 transgenic mice.
(G) Modulation of Wip1 levels is sufficient to regulate islet regenerative capacity with advancing age. Six- to eight-month-old WT and UbC-Wip1 mice were injected with STZ and glucose levels were monitored every week. *p < 0.05.
(H) Functional Model of Wip1 and p38MAPK in aging. In young mice, high level of Wip1 contributes to inhibition of p38 activation. Inhibition of p38 prevents Bmi1 from becoming phosphorylated and lead to strong association of Bmi1 with chromatin at CDKN2A locus and results in repression of transcription of cell cycle inhibitors p16Ink4a and p14ARF. Consequently self renewal of tissue can take place. Upon aging Wip1 expression decreases and promotes p38 activation. p38 transduces signal to MK2/MK3 kinases to phosphorylate Bmi1 which results in release of Bmi1 from chromatin. Absence of Bmi1 on chromatin will contribute to activation of transcription of p16Ink4 and p14ARF thereby promoting cell cyle arrest, inhibition of tissue self renewal and aging.
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