apoB and apobec1, two genes key to lipid metabolism, are transcriptionally regulated by p53.
p53 is an established tumor suppressor gene activating the transcription of multiple target genes. Apolipoprotein B (apo B), a dietary lipid transporter, occurs as apo B-100 and apoB-48, created by a premature stop codon by apo B mRNA-editing enzyme complex 1 (apobec1). We have identified p53 response elements (p53RE) in the genes encoding for apoB and apobec1, cloned these novel p53RE and by performing functionality, chromatin immunoprecipitation (ChIP) and expression assays in cancer cell lines, confirmed that these genes are transcriptionally regulated by p53. In C57bl/6 mice treated with adriamycin, a potent p53 inducer, intestinal/liver mRNA expression of apoB and apobec1 and liver apoB editing levels were elevated. In irradiated wild type C57bl6 mice but not p53 knockout mice, liver and intestine apoB but not apobec1 mRNA expression was elevated. In this work, we have identified that p53 regulates the transcription of two central lipid metabolism players. We further show, for the first time, an involvement of p53 in the RNA editing process, through the transcription of apobec1. Our findings may reveal a previously unknown role for p53 in the direct regulation of atherogenic lipoproteins and a possible role for these genes in classical p53 activities.
Ashur-Fabian
Osnat
O
Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel. osnataf@gmail.com
Har-Zahav
Adi
A
Shaish
Aviv
A
Wiener Amram
Hila
H
Margalit
Ofer
O
Weizer-Stern
Orly
O
Dominissini
Dan
D
Harats
Dror
D
Amariglio
Ninette
N
Rechavi
Gideon
G
D000071479:APOBEC-1 Deaminase; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D001055:Apolipoproteins B; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase