title: Salivary protein histatin 3 regulates cell proliferation by enhancing p27(Kip1) and heat shock cognate protein 70 ubiquitination.
abstract: Histatins are salivary proteins with antimicrobial activities. We previously reported that histatin 3 binds to heat shock cognate protein 70 (HSC70), which is constitutively expressed, and induces DNA synthesis stimulation and promotes human gingival fibroblast (HGF) survival. However, the underlying mechanisms of histatin 3 remain largely unknown. Here, we found that the KRHH sequence of histatin 3 at the amino acid positions 5-8 was essential for enhancing p27(Kip1) (a cyclin-dependent kinase inhibitor) binding to HSC70 that occurred in a dose-dependent manner; histatin 3 enhanced the binding between p27(Kip1) and HSC70 during the G1/S transition of HGFs as opposed to histatin 3-M(5-8) (substitution of KRHH for EEDD in histatin 3). Histatin 3, but not histatin 3-M(5-8), stimulated DNA synthesis and promoted HGF survival. Histatin 3 dose-dependently enhanced both p27(Kip1) and HSC70 ubiquitination, whereas histatin 3-M(5-8) did not. These findings provide further evidence that histatin 3 may be involved in the regulation of cell proliferation, particularly during G1/S transition, via the ubiquitin-proteasome system of p27(Kip1) and HSC70.
authors.affiliation: Department of Pharmacology, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan. Electronic address: yimamura@po.mdu.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Department of Bacteriology, Osaka Dental University, Hirakata, Osaka 573-1121, Japan.
authors.forename: Pao-Li
authors.initials: PL
authors.lastname: Wang
authors.affiliation: Department of Dental Education Innovation, Osaka Dental University, Hirakata, Osaka 573-1121, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Masuno
authors.affiliation: Department of Pharmacology, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Sogawa
mesh_terms: D001665:Binding Sites; D049109:Cell Proliferation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D057809:HEK293 Cells; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D054808:Histatins / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D012471:Salivary Proteins and Peptides / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: C436291:CDKN1B protein, human; D050883:HSC70 Heat-Shock Proteins; C068075:HTN3 protein, human; D054808:Histatins; D012471:Salivary Proteins and Peptides; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: HSC70; Histatin; Ubiquitin; p27(Kip1)