Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer.
We identified IFIX as a new member of the hematopoietic interferon (IFN)-inducible nuclear protein with the 200-amino-acid repeat (HIN-200) family. Six different alternatively spliced forms of mRNA are transcribed from the IFIX gene, which are predicted to encode six different isoforms of IFIX proteins (IFIXalpha1, alpha2, beta1, beta2, gamma1, and gamma2). The IFIX proteins are primarily localized in the nucleus. They share a common N-terminal region that contains a predicted pyrin domain and a putative nuclear localization signal. Unlike IFIXalpha and IFIXbeta, IFIXgamma isoforms do not have the 200-amino-acid signature motif. Interestingly, the expression of IFIX was reduced in most human breast tumors and breast cancer cell lines. Expression of IFIXalpha1, the longest isoform of IFIX, in human breast cancer cell lines reduced their anchorage-dependent and -independent growth in vitro and tumorigenicity in nude mice. Moreover, a liposome-mediated IFIXalpha1 gene transfer suppressed the growth of already-formed tumors in a breast cancer xenograft model. IFIXalpha1 appears to suppress the growth of breast cancer cells in a pRB- and p53-independent manner by increasing the expression of the cyclin-dependent kinase inhibitor p21(CIP1), which leads to the reduction of the kinase activity of both Cdk2 and p34(Cdc2). Together, our results show that IFIXalpha1 possesses a tumor-suppressor activity and suggest IFIXalpha1 may be used as a therapeutic agent in cancer treatment.
Ding
Yi
Y
1Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Wang
Li
L
Su
Li-Kuo
LK
Frey
Jennifer A
JA
Shao
Ruping
R
Hunt
Kelly K
KK
Yan
Duen-Hwa
DH
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy; D016203:CDC2 Protein Kinase / Q000378:metabolism; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D015197:Carcinogenicity Tests; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C101635:HIN-200 protein, human; C484444:HIN-200 protein, mouse; D009687:Nuclear Proteins; C487565:PYHIN1 protein, human; D020033:Protein Isoforms; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2