The hKLK3 gene coding for the tumour marker PSA (Prostate-specific antigen) is a multiply spliced gene.

N. Heuze-Vourc'h, V. Leblond, S. Olayat, N. Gutman, F. Arnold and Y. Courty

Laboratoire d'Enzymologie et Chimie des Proteines, EMI-U 0010, Faculte de Medecine, Tours, France.

AIM : Prostate-specific antigen (PSA) is a serine protease widely used as serum marker for detection of prostate tumours. PSA is present in serum as a mixture of different molecular species and identification of each form appears of high interest since the proportion of some species differs in benign prostatic hyperplasia and cancer. We questioned whether this PSA heterogeneity resulted from alternative splicing of the hKLK3 gene. METHODS AND RESULTS: Combined Northern blotting, molecular cloning and database searching analyses showed that the hKLK3 gene products comprise at least 13 transcripts ranging from 0.7 kb to 6.1 kb. Ten transcripts were sequenced and the predicted proteins were identified as PSA and 5 alternate proteins. All the transcripts resulted from alternative splicing or polyadenylation. Four predicted proteins are variants of PSA and were designated as PSA-RP1 to PSA-RP4 (PSA-related protein). All these variants might be synthesised like PSA as a prepro-form containing 238, 180, 218, and 220 amino acids, respectively. PSA-RP1 and PSA-RP2 have an alternate C-terminal tail and lack the serine residue essential to confer the catalytic activity of PSA. PSA-RP3 and PSA-RP4 have internal deletions including the N-glycosylation site (PSA-RP3) or the Asp-96 residue of the catalytic triad (PSA-RP4). The fifth predicted protein is encoded by a transcript retaining intron 1. This predicted protein of 103 amino acids is unrelated to PSA. CONCLUSION: We showed that the hKLK3 gene can generate a diverse collection of proteins related to PSA. Complementary studies would be required to determine the clinical significance and usefulness of PSA splicing heterogeneity.

KEY WORDS: gene expression, serum marker.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Diagnostic Markers.

This presentation received an honorable mention in our poster contest and was recognized with the Symposium Presidents' Award for Scientific Excellence.