Alternative titles; symbols
HGNC Approved Gene Symbol: KLK3
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:50,854,915-50,860,764 (from NCBI)
Human prostate-specific antigen (APS) is a kallikrein-like protease present in seminal plasma. It is a single-chain glycoprotein with a molecular mass of about 33 kD that may function normally in the liquefaction of seminal coagulum. Radioimmunoassay of serum levels of this antigen (called PSA in the clinical setting) is useful in the diagnosis and monitoring of prostatic carcinoma (Stamey et al., 1987; Oesterling et al., 1988).
Lundwall and Lilja (1987) cloned a cDNA corresponding to APS, and Schulz et al. (1988) reported the complete sequence of a cDNA encompassing the immature human prostate-specific antigen and an unspliced leader sequence.
Riegman et al. (1989) used APS cDNA fragments as hybridization probes to isolate a clone encoding the APS protein from a human genomic DNA library. Variant APS cDNAs can be explained by intron retention and alternative splicing of the primary transcript.
Gan et al. (2000) reported that the full-length KLK3 protein contains 261 amino acids. It has a putative signal peptide, followed by a short activating peptide and the protease domain, which includes the catalytic triad of his65, asp120, and ser213. RT-PCR of 35 adult and fetal tissues detected highest expression in prostate. Expression was weak in colon, mammary gland, and parotid, and little to no expression was detected in other tissues examined.
By searching databases for prostate-specific transcripts, David et al. (2002) identified an alternatively spliced KLK3 transcript, which they called PSA-linked molecule (PSALM), arising from the use of an alternate donor site within intron 1. The transcript contains a sequence from intron 1 linked to exon 1. The deduced protein contains 104 amino acids and has a calculated molecular mass of 11 kD. PSALM shares only the N-terminal 15-amino acid signal peptide with the original PSA protein; the mature proteins display no similarity. However, PSALM shares 32% amino acid identity with a comparable KLK2 (147960) splice variant that David et al. (2002) designated KLM. Both variants are rich in proline and serine/threonine residues. Of the 12 tissues examined by RT-PCR, only prostate and the prostate-derived cell line LNCaP expressed PSALM. Northern blot analysis detected intron 1-containing transcripts of 3.0, 5.0, and 6.5 kb. In situ hybridization of prostate sections indicated that the PSALM transcript was expressed in secretory epithelial cells of the prostate tubule. PSALM was secreted from transfected LNCaP cells.
PSA expression can be regulated by androgens. Riegman et al. (1991) and Cleutjens et al. (1996) identified 2 functional androgen-response elements (AREs) in the proximal promoter of the PSA gene at positions -170 and -394. To detect additional, more distal control elements, Cleutjens et al. (1997) mapped DnaseI-hypersensitive sites (DHSs) upstream of the PSA gene in chromatin from the prostate-derived cell line LNCaP grown in the presence or absence of the synthetic androgen R1881. In a region 3.8 to 4.8 kb upstream of the PSA transcription start site, a cluster of 3 DHSs was detected. The middle DHS (DHSII, at -4.2 kb) showed strong androgen responsiveness. Further analysis of the DHSII region indicated the presence of a complex, androgen-responsive and cell-specific enhancer. In transiently transfected cells, PSA promoter constructs showed approximately 3,000-fold higher activity in the presence than in the absence of R1881. The core region of the enhancer could be mapped within a 440-bp fragment. A functionally active, high-affinity androgen receptor binding site (GGAACATATTGTATC) was identified in the center of this fragment and mutation of this element almost completely abolished PSA promoter activity.
APS, present at very low concentrations in female serum, can be measured with highly sensitive immunoassays. Melegos et al. (1997) found that in female tissues, the APS gene is regulated by steroid hormones. They studied the association of serum APS with hyperandrogenic states in females and found that APS levels were higher in hirsute women compared to controls. They concluded that serum APS may be a biochemical marker of androgen excess in females.
Bansal et al. (2000) investigated the interrelationships of age, PSA, and various zonal measurements in the prostate, and assessed the impact of heritable influences on total PSA. Eighty-four monozygotic twin pairs and 83 dizygotic twin pairs were studied, and serum total PSA, free PSA, and PSA-alpha-1-antichymotrypsin were measured. Their prostate volumes (total (TV), transition zone (TZ), and peripheral zone) were quantitated using transrectal ultrasound. Total PSA was significantly correlated with all zonal prostate measurements (TZ, peripheral zone, TV, and TZ/TV) and with age. When linear regression was applied, only age and TZ were retained in the final model. The proportion of variability in total PSA explained by these 2 factors, however, was below 24%. In contrast, estimates of heritability showed that approximately 45% of the variability in total PSA could be explained by inherited factors.
Using Northern blot analysis, David et al. (2002) determined that expression of the PSALM variant of KLK3 was upregulated in transfected LNCaP cells in response to androgen stimulation.
Wang et al. (2005) found that androgen receptor (AR; 313700) regulation of PSA in LNCaP cells involved both a promoter-proximal sequence and an enhancer about 4 kb upstream. Recruitment of AR and essential coactivators at both sites created a chromosomal loop that allowed RNA polymerase II (pol II; see 180660) to track from the enhancer to the promoter. Phosphorylation of the RNA pol II C-terminal domain was required for RNA pol II tracking but not chromosomal looping.
Riegman et al. (1989) determined that the APS gene spans about 6 kb and contains 5 exons.
Sutherland et al. (1988) used in situ hybridization and Southern analysis of a human/mouse somatic cell hybrid panel to map the APS gene to 19q13. In both mouse and man, the APS and KLK1 (147910) genes mapped to the same region; the homologous mouse loci are on chromosome 7. Indeed, the mouse glandular kallikrein gene family consists of 24 genes (12 functional and 12 pseudogenes) which are all closely linked (Evans et al., 1987).
By sequencing the kallikrein gene cluster on chromosome 19q13, Gan et al. (2000) identified 13 kallikrein-related genes and 5 pseudogenes.
Bansal, A., Murray, D. K., Wu, J. T., Stephenson, R. A., Middleton, R. G., Meikle, A. W. Heritability of prostate-specific antigen and relationship with zonal prostate volumes in aging twins. J. Clin. Endocr. Metab. 85: 1272-1276, 2000. [PubMed: 10720075] [Full Text: https://doi.org/10.1210/jcem.85.3.6399]
Cleutjens, K. B. J. M., van der Korput, H. A. G. M., van Eekelen, C. C. E. M., van Rooij, H. C. J., Faber, P. W., Trapman, J. An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Molec. Endocr. 11: 148-161, 1997. [PubMed: 9013762] [Full Text: https://doi.org/10.1210/mend.11.2.9883]
Cleutjens, K. B. J. M., van Eekelen, C. C. E. M., van der Korput, H. A. G. M., Brinkmann, A. O., Trapman, J. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J. Biol. Chem. 271: 6379-6388, 1996. [PubMed: 8626436] [Full Text: https://doi.org/10.1074/jbc.271.11.6379]
David, A., Mabjeesh, N., Azar, I., Biton, S., Engel, S., Bernstein, J., Romano, J., Avidor, Y., Waks, T., Eshhar, Z., Langer, S. Z., Lifschitz-Mercer, B., Matzkin, H., Rotman, G., Toporik, A., Savitsky, K., Mintz, L. Unusual alternative splicing within the human kallikrein genes KLK2 and KLK3 gives rise to novel prostate-specific proteins. J. Biol. Chem. 277: 18084-18090, 2002. [PubMed: 11834722] [Full Text: https://doi.org/10.1074/jbc.M102285200]
Evans, B. A., Drinkwater, C. C., Richards, R. I. Mouse glandular kallikrein genes: structure and partial sequence analysis of the kallikrein gene locus. J. Biol. Chem. 262: 8027-8034, 1987. [PubMed: 3036794]
Gan, L., Lee, I., Smith, R., Argonza-Barrett, R., Lei, H., McCuaig, J., Moss, P., Paeper, B., Wang, K. Sequencing and expression analysis of the serine protease gene cluster located in chromosome 19q13 region. Gene 257: 119-130, 2000. [PubMed: 11054574] [Full Text: https://doi.org/10.1016/s0378-1119(00)00382-6]
Lundwall, A., Lilja, H. Molecular cloning of human prostate specific antigen cDNA. FEBS Lett. 214: 317-322, 1987. [PubMed: 2436946] [Full Text: https://doi.org/10.1016/0014-5793(87)80078-9]
Melegos, D. N., Yu, H., Ashok, M., Wang, C., Stanczyk, F., Diamandis, E. P. Prostate-specific antigen in female serum, a potential new marker of androgen excess. J. Clin. Endocr. Metab. 82: 777-780, 1997. [PubMed: 9062481] [Full Text: https://doi.org/10.1210/jcem.82.3.3792]
Oesterling, J. E., Chan, D. W., Epstein, J. I., Kimball, A. W., Jr., Bruzek, D. J., Rock, R. C., Brendler, C. B., Walsh, P. C. Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J. Urol. 139: 766-772, 1988. [PubMed: 2451037] [Full Text: https://doi.org/10.1016/s0022-5347(17)42630-9]
Riegman, P. H. J., Vlietstra, R. J., van der Korput, J. A. G. M., Brinkmann, A. O., Trapman, J. The promoter of the prostate-specific antigen gene contains a functional androgen responsive element. Molec. Endocr. 5: 1921-1930, 1991. [PubMed: 1724287] [Full Text: https://doi.org/10.1210/mend-5-12-1921]
Riegman, P. H. J., Vlietstra, R. J., van der Korput, J. A. G. M., Romijn, J. C., Trapman, J. Characterization of the prostate-specific antigen gene: a novel human kallikrein-like gene. Biochem. Biophys. Res. Commun. 159: 95-102, 1989. [PubMed: 2466464] [Full Text: https://doi.org/10.1016/0006-291x(89)92409-1]
Schulz, P., Stucka, R., Feldmann, H., Combriato, G., Klobeck, H.-G., Fittler, F. Sequence of a cDNA clone encompassing the complete mature human prostate specific antigen (PSA) and an unspliced leader sequence. Nucleic Acids Res. 16: 6226 only, 1988. [PubMed: 2456523] [Full Text: https://doi.org/10.1093/nar/16.13.6226]
Stamey, T. A., Yang, N., Hay, A. R., McNeal, J. E., Freiha, F. S., Redwine, E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. New Eng. J. Med. 317: 909-916, 1987. [PubMed: 2442609] [Full Text: https://doi.org/10.1056/NEJM198710083171501]
Sutherland, G. R., Baker, E., Hyland, V. J., Callen, D. F., Close, J. A., Tregear, G. W., Evans, B. A., Richards, R. I. Human prostate-specific antigen (APS) is a member of the glandular kallikrein gene family at 19q13. Cytogenet. Cell Genet. 48: 205-207, 1988. [PubMed: 2470553] [Full Text: https://doi.org/10.1159/000132629]
Wang, Q., Carroll, J. S., Brown, M. Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Molec. Cell 19: 631-642, 2005. [PubMed: 16137620] [Full Text: https://doi.org/10.1016/j.molcel.2005.07.018]