Review
The New Human Kallikrein Gene Family: Implications in Carcinogenesis

https://doi.org/10.1016/S1043-2760(99)00225-8Get rights and content

Abstract

The traditional human kallikrein gene family consists of three genes, namely KLK1 [encoding human kallikrein 1 (hK1) or pancreatic/renal kallikrein], KLK2 (encoding hK2, previously known as human glandular kallikrein 1) and KLK3 [encoding hK3 or prostate-specific antigen (PSA)]. KLK2 and KLK3 have important applications in prostate cancer diagnostics and, more recently, in breast cancer diagnostics. During the past two to three years, new putative members of the human kallikrein gene family have been identified, including the PRSSL1 gene [encoding normal epithelial cell-specific 1 gene (NES1)], the gene encoding zyme/protease M/neurosin, the gene encoding prostase/KLK-L1, and the genes encoding neuropsin, stratum corneum chymotryptic enzyme and trypsin-like serine protease. Another five putative kallikrein genes, provisionally named KLK-L2, KLK-L3, KLK-L4, KLK-L5 and KLK-L6, have also been identified. Many of the newly identified kallikrein-like genes are regulated by steroid hormones, and a few kallikreins (NES1, protease M, PSA) are known to be downregulated in breast and possibly other cancers. NES1 appears to be a novel breast cancer tumor suppressor protein and PSA a potent inhibitor of angiogenesis. This brief review summarizes recent developments and possible applications of the newly defined and expanded human kallikrein gene locus.

Section snippets

The New Human Kallikrein Gene Locus

We have recently studied a genomic region of approximately 300 kb around human chromosome 19q13.3–13.4 and established the position of each of the known human kallikrein and kallikrein-like genes. In addition, we have identified new members of this gene family, using the method of ‘positional candidate’ cloning7. In Fig. 1, we present the relative localization and direction of transcription of 14 genes that appear to be members of the same family. In Table 1, we present the currently used names

The KLK1 Gene

Pancreatic/renal kallikrein (hK1) is found in various tissues (salivary glands, pancreas, kidney, heart, etc.) and catalyzes the release of lysyl-bradykinin or bradykinin from low- and high-molecular weight kininogen1, 2. Bradykinin is involved in a number of physiological and pathological processes, including control of blood flow, vascular tone, inflammation and cell proliferation. Because the KLK1 gene is expressed abundantly in many tissues, it has not found any specific applications in

The KLK3 Gene

The KLK3 gene encodes PSA, which is the best cancer marker currently available, and it is widely used for screening, diagnosis and management of prostate cancer. There are numerous recent reviews of this molecule5, 6, 8 and of its clinical applications. More recently, PSA has been identified in normal, hyperplastic and cancerous breast tissues9, 10. PSA is a favorable prognostic indicator in breast cancer, and its synthesis is generally reduced in breast cancer compared with normal or

The KLK2 Gene

The KLK2 gene (encoding hK2) is located at the same chromosomal region as KLK3 (only 13 kb further telomeric) and has 80% homology with KLK3. An extensive review of the literature regarding hK2 has been published recently6. Only within the past two to three years has it been possible to measure hK2 with immunological techniques18, 19, 20. Human glandular kallikrein is now emerging as an additional prostatic tumor marker that might have clinical applications complementary to those of PSA, as

The Gene Encoding Prostase/KLK-L1

This gene is known as the KLK-L1/KLK4 gene. It was cloned independently by Nelson et al., who used subtractive hybridization28, and by our own group (using the positional candidate approach7, 29), as well as by others30. On the basis of northern blot analysis, it appeared initially that this gene was expressed predominantly, if not exclusively, in prostatic tissue. However, with the use of the more sensitive reverse transcription polymerase chain reaction (RT–PCR) technique, we found that this

The Gene Encoding Zyme/Protease M/Neurosin

This gene, now known as PRSS9 (for protease, serine, 9), was cloned independently by three different groups and was given three different names31, 32, 33. One group cloned this gene by the method of differential display, as a gene that is expressed differently in normal human mammary epithelial cells (high expression) versus tumor cell lines (low expression)31. PRSS9 encodes a serine protease and maps very close to the human kallikrein gene locus31, 32. The gene has about 50% homology with the

The Gene Encoding Human Stratum Corneum Chymotryptic Enzyme (HSCCE)

HSCCE is a new serine proteinase produced by keratinocytes in the epidermis35, 36. The gene encoding this proteinase is known as PRSS6. The putative function of the protein is to catalyze the degradation of intercellular cohesive structures in the cornified layer of the skin, thus facilitating the continuous shedding of cells from the skin surface. HSCCE is found mainly in human skin, the central nervous system, kidney, mammary gland, thymus and salivary glands. One of the possible functions of

The Gene Encoding Neuropsin

This gene is now known as PRSS19. Neuropsin is a serine protease that is thought to function in a number of different tissues, including the skin and brain. In mice, this protease has been shown to have important roles in neural plasticity38, 39, 40. The human gene has 72% homology with cDNA encoding murine neuropsin and the highest level of expression is also seen in brain and skin. Neuropsin might be involved in the production of cerebrospinal fluid, the formation of memory, and in some forms

The Gene Encoding NES1

This gene was cloned by Vimla Band and her associates using subtractive hybridization techniques41 and is now known as PRSSL1. The discovery of this gene was based on the finding that it was expressed abundantly in a normal breast cell line but was absent from the same cell line that had been irradiated to become tumorous. Thus, it was suggested that the downregulation of PRSSL1 might be part of the tumorous phenotype in this cell line. This was confirmed by expression studies, which indicated

The Gene Encoding Trypsin-like Serine Protease (TLSP)

Recently, Yoshida et al. cloned a novel human cDNA that encodes a putative novel serine protease, TLSP (Ref. 45). This gene is now known as PRSS20 and is expressed primarily in the brain and in keratinocytes. It appears to have a number of important similarities to neuropsin. There are no reports yet describing the connection of this gene to any human disease.

Newly Identified Kallikrein-like Genes

As shown in Fig. 1, another six kallikrein-like genes have been discovered within the human kallikrein gene locus7. These genes are dispersed throughout the 300-kb genomic region between the classic kallikrein genes and other genes previously identified and described in this review. All these new genes are predicted to encode serine proteases and have significant homologies, at both the DNA and amino acid level, with the classic kallikreins (GenBank accession numbers AF135023, AF135024,

Connection of the Human Kallikrein Gene Family to Cancer: An Integrated View

The connection between breast and prostate cancer and steroid hormones has been established in many epidemiological studies, but we do not yet understand which genes are involved in the pathogenesis of the sporadic forms of these two diseases48. It is logical to speculate that at least some of the genes involved in the pathogenesis of breast and prostatic cancer are regulated directly or indirectly through the action of steroid hormones. In this respect, the KLK3, KLK2, KLK-L1/KLK4, PRSS9,

Conclusion: Future Directions

We have provided evidence that the human kallikrein gene family consists of as many as 14 genes. Some of these genes have been identified only recently and not much is known about their expression, hormonal regulation or involvement in human diseases. On the other hand, there is convincing evidence that at least some kallikreins, including PSA, NES1 and zyme/protease M/neurosin, are involved in breast and prostate cancer in a way that is reminiscent of tumor suppressor activity. Some of the

References (48)

  • C. Shimizu

    Characterization of recombinant and brain neuropsin, a plasticity-related serine protease

    J. Biol. Chem.

    (1998)
  • S. Yoshida

    Sequence analysis and expression of human neuropsin cDNA and gene

    Gene

    (1998)
  • L. Luo

    Structural characterization and mapping of the normal epithelial cell-specific 1 gene

    Biochem. Biophys. Res. Commun.

    (1998)
  • S. Yoshida

    cDNA cloning and expression of a novel serine protease, TSLP

    Biochim. Biophys. Acta

    (1998)
  • G.M. Yousef et al.

    The new kallikrein-like gene KLK–L2: molecular characterization, mapping, tissue expression and hormonal regulation

    J. Biol. Chem.

    (1999)
  • J.A. Clements

    The molecular biology of the kallikreins and their roles in inflammation

  • K.D. Bhoola

    Bioregulation of kinins: kallikreins, kininogens and kininases

    Pharmacol. Rev.

    (1992)
  • H.G. Rittenhouse

    Human kallikrein 2 (hK2) and prostate-specific antigen (PSA); two closely related, but distinct, kallikreins in the prostate

    Crit. Rev. Clin. Lab. Sci.

    (1998)
  • G.M. Yousef

    Identification of novel human kallikrein-like genes on chromosome 19q13.3–q13.4

    Anticancer Res.

    (1999)
  • E.P. Diamandis et al.

    New biological functions of prostate specific antigen?

    J. Clin. Endocrinol. Metab.

    (1995)
  • Diamandis, E.P. and Yu, H. (1997) Non-prostatic sources of prostate-specific antigen. In The Urologic Clinics of North...
  • H. Yu

    Prostate specific antigen is a new favourable prognostic indicator for women with breast cancer

    Cancer Res.

    (1995)
  • H. Yu

    Prognostic value of prostate-specific antigen for women with breast cancer. A large U.S. cohort study

    Clin. Cancer Res.

    (1998)
  • N. Zarghami

    Steroid hormone regulation of prostate specific antigen gene expression in breast cancer

    Br. J. Cancer

    (1997)
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