The human 1-8D gene (IFITM2) is a novel p53 independent pro-apoptotic gene.
The human 1-8 interferon inducible gene family consists of at least 3 functional genes; 9-27, 1-8D and 1-8U, which are all linked on an 18-kb fragment of chromosome 11 and are highly homologous. It has recently been shown by us and others that the 1-8D gene is overexpressed in colon carcinoma. Here, we show, by sequence comparison of the 1-8D in pairs of tumor/normal colon tissues, the existence of 6 different alleles, containing single-nucleotide polymorphisms with no mutations. Transformation assays revealed a possible role for the 1-8D gene as a transformation inhibitor. Further, transient expression of the human 1-8D gene in multiple mammalian cell lines showed accumulation of cells in the G1 phase followed by elevation in the subG1 phase. SubG1 elevation was confirmed as apoptosis by Annexin-V binding assays and transferase-mediated dUTP nick end labeling assays. Moreover, knock-down of 1-8D provided partial protection from Etoposide and UV-induced apoptosis. The induction of apoptosis by 1-8D is dependent on caspase activities but not on p53 expression. Although 1-8D induces apoptosis independently of p53, p53 expression downregulates 1-8D protein expression. Our data suggest a role for the 1-8D gene as a novel pro-apoptotic gene that will provide new insights into the regulated cellular pathways to death.
Daniel-Carmi
Vered
V
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Makovitzki-Avraham
Efrat
E
Reuven
Eliran-Moshe
EM
Goldstein
Ido
I
Zilkha
Noga
N
Rotter
Varda
V
Tzehoval
Esther
E
Eisenbach
Lea
L
D000595:Amino Acid Sequence; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D017304:Annexin A5; C080081:IFITM2 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D020169:Caspases