title: Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer.
abstract: Kallikreins (KLKs) are highly conserved serine proteases that play key roles in a variety of physiological and pathological processes. KLKs are secreted proteins that have extracellular substrates and function. For example, prostate-specific antigen (or KLK3) is a secreted protein that is widely used as a diagnostic marker for prostate cancer. KLK4 is a recently identified member of the kallikrein family that is regulated by androgens and is highly specific to prostate for expression. Here, we show that the gene product of KLK4, hK4, is the first member of the KLK family that is intracellularly localized. We provide strong evidence that the previously assigned first exon that was predicted to code for a signal peptide that would target hK4 for secretion is not part of the physiologically relevant form of KLK4 mRNA. In addition to detailed mapping of the KLK4 mRNA 5' end by RT-PCR, this conclusion is supported by predominantly nuclear localization of the hK4 protein in the cell, documented by both immunofluorescence and cell fractionation experiments. Furthermore, in addition to androgens, hK4 expression is regulated by estrogen and progesterone in prostate cancer cells. Finally, in situ hybridization on normal and hyperplastic prostate samples in tissue microarrays indicate that KLK4 is predominantly expressed in the basal cells of the normal prostate gland and overexpressed in prostate cancer. These data suggest that KLK4 has a unique structure and function compared with other members of the KLK family and may have a role in the biology and characterization of prostate cancer.
authors.affiliation: Department of Biology, University of Oslo, Oslo, Norway.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Xi
authors.forename: Tove Irene
authors.initials: TI
authors.lastname: Klokk
authors.forename: Kemal
authors.initials: K
authors.lastname: Korkmaz
authors.forename: Piotr
authors.initials: P
authors.lastname: Kurys
authors.forename: Cem
authors.initials: C
authors.lastname: Elbi
authors.forename: Bjørn
authors.initials: B
authors.lastname: Risberg
authors.forename: Håvard
authors.initials: H
authors.lastname: Danielsen
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Fahri
authors.initials: F
authors.lastname: Saatcioglu
mesh_terms: D000818:Animals; D019556:COS Cells; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D002522:Chlorocebus aethiops; D005091:Exons; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D007610:Kallikreins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000201:enzymology / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D009687:Nuclear Proteins; D012333:RNA, Messenger; D007610:Kallikreins; C120801:kallikrein 4