title: Interferon-alpha2b induces p21cip1/waf1 degradation and cell proliferation in HeLa cells.
abstract: Type I interferons (IFNs) are a family of cytokines that exhibit various biological activities. Besides their roles in immune response, IFNs have been known to modulate cell proliferation and to induce apoptosis. Thus, IFNs are used as an antitumor agent against certain types of cancer, but it is unclear why many other cancers are not influenced by IFNs. Here, we found that IFN-alpha2b, a subfamily of IFN-alpha, enhanced proliferation of HeLa cells, a cell line derived from human cervical cancer. IFN-alpha2b was rather inhibitory on the growth of other types of cervical cancer cells including those positive for HPV. Among the proliferation- and the apoptosis-related genes, p21(cip1/waf1) (p21) was upregulated by IFN-alpha2b, whereas p53, p27 or BCL-2 associated X protein (BAX) was not affected. IFN-alpha2b did not alter promoter activities of p21 but did prolong the decay of p21 mRNA. In contrast, the level of p21 protein was lowered by IFN-alpha2b, and half-life analysis of p21 protein revealed that IFN-alpha2b enhances p21 protein instability in HeLa cells. Pretreatment of the cells with MG132, a proteasome inhibitor, abolished the IFN-alpha2b-mediated p21 degradation, suggesting that IFN-alpha2b accelerated the ubiquitin-proteasome dependent degradation of p21. Consistent with these results, IFN-alpha2b increased S-phase cell cycle distribution in HeLa cells. In addition, IFN-alpha2b liberated the cells from G(1)-phase arrest by 5-fluorouracil (5-FU) and from G(2)-phase arrest by paclitaxel. These results provide a novel role of Type I IFNs in cell cycle regulation and may define an importance of individualized IFN-based therapy against specific types of cancer.
authors.affiliation: Department of Gastroenterology and Hematology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ota
authors.forename: Tomoh
authors.initials: T
authors.lastname: Matsumiya
authors.forename: Hirotake
authors.initials: H
authors.lastname: Sakuraba
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Hidemi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Shogo
authors.initials: S
authors.lastname: Kawaguchi
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Fukuda
authors.forename: Kei
authors.initials: K
authors.lastname: Satoh
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D016898:Interferon-alpha / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D055550:Protein Stability / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016898:Interferon-alpha; D007976:Leupeptins; D061988:Proteasome Inhibitors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde