GART mediates the renewal of intestinal epithelial barrier via p38/p53/PUMA cascade in colitis

Jian-An Bai; Hua Jie; Sun Wei; Shidong Wang; Huarui Guo; Qiyun Tang

doi:10.1007/s10495-016-1301-y

GART mediates the renewal of intestinal epithelial barrier via p38/p53/PUMA cascade in colitis

Apoptosis. 2016 Dec;21(12):1386-1397. doi: 10.1007/s10495-016-1301-y.

Authors

Jian-An Bai¹, Hua Jie², Sun Wei², Shidong Wang³, Huarui Guo³, Qiyun Tang⁴

Affiliations

¹ Sir Run Run Hospital, Nanjing Medical University, No.109 Longmian Road, Nanjing, Jiangsu, China.
² The First Affiliated Hospital with Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu, China.
³ Linyi county people's hospital, Dezhou, Shandong, China.
⁴ The First Affiliated Hospital with Nanjing Medical University, No.300, Guangzhou Road, Nanjing, Jiangsu, China. tqy831@163.com.

PMID: 27718035
DOI: 10.1007/s10495-016-1301-y

Abstract

Glycinamide ribonucleotide formyltransferase (GART) has been established as a pivotal enzyme in de novo purine synthesis, and mediates cellular apoptosis in many diseases. We aimed to investigate the role of GART in the pathogenesis of Crohn's disease (CD). In our study, we demonstrated for the first time that GART expression is up-regulated in patients with active CD and in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced acute colitis model. Moreover, the inhibition of GART induced cellular apoptosis and suppressed the migration of IECs through the activation of the MEKK3-MKK3-p38 mitogen-activated protein kinase (MAPK) pathway, following with the dys-regulation of p53 and p53 up-regulated modulator of apoptosis (PUMA). Taken together, GART plays a critical role in the protection of cellular apoptosis and migration of intestinal epithelial cells to maintain the integrity of the epithelial barrier, thus providing a new potential approach in designing a novel therapy for CD.

Keywords: Apoptosis; Crohn’s disease; Glycinamide ribonucleotide formyltransferase; Intestinal epithelial cells; P38; P53.

MeSH terms

Apoptosis
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Carbon-Nitrogen Ligases / genetics
Carbon-Nitrogen Ligases / metabolism*
Cell Proliferation
Colitis / enzymology
Colitis / genetics
Colitis / metabolism*
Colitis / physiopathology
Epithelial Cells / cytology
Epithelial Cells / enzymology
Epithelial Cells / metabolism*
Humans
Intestinal Mucosa / metabolism*
Intestines / cytology
Intestines / enzymology
MAP Kinase Signaling System
Phosphoribosylglycinamide Formyltransferase / genetics
Phosphoribosylglycinamide Formyltransferase / metabolism*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

Apoptosis Regulatory Proteins
BBC3 protein, human
Proto-Oncogene Proteins
TP53 protein, human
Tumor Suppressor Protein p53
Phosphoribosylglycinamide Formyltransferase
p38 Mitogen-Activated Protein Kinases
Carbon-Nitrogen Ligases
GART protein, human