Schlafen 3, a novel gene, regulates colonic mucosal growth during aging.
Although aging is associated with increased proliferation and decreased apoptosis in the colonic mucosa of Fischer 344 rats, the regulatory mechanisms are poorly understood. Gene expression profiling (Illumina platform) was carried out in freshly isolated colonic mucosal cells from young (4-6 mo old) and aged (22-24 mo old) Fischer 344 rats. Sixty-six genes were differentially expressed in the colonic mucosa between young and old animals (P<0.05). In particular, the expression of schlafen 3, a negative regulator of proliferation, was decreased by 8- to 10-fold in the colonic mucosa of aged rats. Administration of wortmannin, which inhibited colonic mucosal proliferation in the colonic mucosa of aged rats, stimulated the expression of schlafen 3, indicating a growth regulatory role of this gene. To further determine the growth regulatory properties of schlafen 3 gene, schlafen 3 cDNA was transfected in colon cancer HCT-116 cells. This resulted in a 30-40% inhibition of cellular growth, accompanied by decreased expression of PCNA and cyclin D1 and reduced phosphorylation of retinoblastoma protein. In conclusion, our present study demonstrates that several genes involved in proliferation and apoptosis are differentially expressed in the colonic mucosa of young and aged rats. Schlafen 3, a novel negative regulator of growth, which is markedly downregulated in the colonic mucosa of the aged, may play a role in regulating colonic mucosal growth during aging.
Patel
Bhaumik B
BB
Veterans Administration Medical Center, Department of Medicine, Karmanos Cancer Institue, Wayne State University, 4646 John R St., Detroit, MI 48201, USA.
Yu
Yingjie
Y
Du
Jianhua
J
Rishi
Arun K
AK
Sarkar
Fazlul H
FH
Tarca
Adi L
AL
Wali
Anil
A
Majumdar
Adhip P N
AP
D000375:Aging; D000818:Animals; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013831:Thiamine / Q000031:analogs & derivatives / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins
D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D013831:Thiamine; C541111:Slfn4 protein, rat; C013835:benphothiamine; C000656172:SLFN12 protein, human; D047908:Intracellular Signaling Peptides and Proteins