News archives


OCTOBER - DECEMBER 17

JULY - SEPTEMBER 17

APRIL - JUNE 17

JANUARY - MARCH 17

OCTOBER - DECEMBER 16

JULY - SEPTEMBER 16

APRIL - JUNE 16

JANUARY - MARCH 16

OCTOBER - DECEMBER 15

JULY - SEPTEMBER 15

APRIL - JUNE 15

JANUARY - MARCH 15

OCTOBER - DECEMBER 14

JULY - SEPTEMBER 14

APRIL - JUNE 14

JANUARY - MARCH 14

OCTOBER - DECEMBER 13

JULY - SEPTEMBER 13

APRIL - JUNE 13

JANUARY - MARCH 13

OCTOBER - DECEMBER 12

JULY - SEPTEMBER 12

APRIL - JUNE 12

JANUARY - MARCH 12

OCTOBER - DECEMBER 11

JULY - SEPTEMBER 11

APRIL - JUNE 11

JANUARY - MARCH 11

OCTOBER - DECEMBER 10

JULY - SEPTEMBER 10

APRIL - JUNE 10

JANUARY - MARCH 10

OCTOBER - DECEMBER 09

JULY - SEPTEMBER 09

APRIL - JUNE 09

JANUARY - MARCH 09

OCTOBER - DECEMBER 08

JULY - SEPTEMBER 08

APRIL - JUNE 08

JANUARY - MARCH 08

OCTOBER - DECEMBER 07

JULY - SEPTEMBER 07

APRIL - JUNE 07

JANUARY - MARCH 07

 
  current news   Press   selected story    
     
  27th July 2009  
 

p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age.

 
 




Authors
Esther Sook Miin Wong1,4, Xavier Le Guezennec1,4, Oleg N. Demidov1, Nicolette Theresa Marshall1, Siew Tein Wang2, Janakiraman Krishnamurthy3, Norman E. Sharpless3, N. Ray Dunn2, and Dmitry V. Bulavin1*

1 Institute of Molecular and Cell Biology (IMCB), Singapore.
2 Institute of Medical Biology (IMB), Singapore.
3 Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The         University of North Carolina School of Medicine, Chapel Hill, NC, USA.
4 These authors contributed equally to this work

*Corresponding author: Dr Dmitry Bulavin, dvbulavin@imcb.a-star.edu.sg


Published in the July 21 print issue of Developmental Cell.

Summary
Aging is a complex organismal process that is controlled by genetic, environmental, and behavioral factors. Accumulating evidence supports a role for different cell cycle inhibitors in mammalian aging. Little is known, however, about the upstream signals that induce their expression. Here, we explore the role of p38MAPK by generating a dominant-negative allele (p38AF) in which activating phosphorylation sites Thr180 and Tyr182 are mutated. Heterozygous p38AF mice show a marked attenuation of p38-dependent signaling and age-induced expression of multiple cell cycle inhibitors in different organs, including pancreatic islets. As a result, aged p38AF/+ mice show enhanced proliferation and regeneration of islets when compared to wild-type littermates. We further find an age-related reduction in expression of the p38-specific phosphatase Wip1. Wip1-deficient mice demonstrate decreased islet proliferation, while Wip1 overexpression rescues aging-related decline in proliferation and regenerative capacity. We propose that modulation of p38MAPK activity may provide new avenues for treating certain age-related degenerative diseases.

 

 
 



 
 


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.


Please click here for press release
For more information on A/Prof. Dmitry Bulavinís lab, Please Click here.