Unusual Alternative Splicing within the Human Kallikrein Genes KLK2 and KLK3 Gives Rise to Novel Prostate-specific Proteins

Abstract

Prostate-specific antigen (PSA) and human kallikrein 2 are closely related products of the human kallikrein genes KLK3 and KLK2, respectively. Both PSA and human kallikrein 2 are produced and secreted in the prostate and have important applications in the diagnosis of prostate cancer. We report here the identification of unusual mRNA splice variants of the KLK2 and KLK3 genes that result from inclusion of intronic sequences adjacent to the first exon. The novel proteins encoded by these transcripts, named PSA-linked molecule (PSA-LM) and hK2-linked molecule (K-LM), share only the signal peptide with the original protein product of the respective gene. The mature proteins are entirely different and bear no similarity to the kallikrein family or to other proteins in the databases. As is the case with PSA, PSA-LM is expressed in the secretory epithelial cells of the prostate and is up-regulated in response to androgenic stimulation. A similar pattern of expression is suggested for K-LM.

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

“…6,[8][9][10][11][12][13][14][15][16] For some cancers, these splicing alterations create functionally significant biomarkers. 9,12,14,[17][18][19][20][21] In light of these studies and the results presented here, we believe that NOTCH2 and FLT3 splicing events are associated with pathogenesis in AML and that identification of the causes and consequences of these splicing alterations will provide a better understanding of the biology of this disease. Because it is well known that splicing alterations can result from mutations and/or could be due to modulated expression of splicing factors, we evaluated whether expression of NOTCH2 and FLT3 splice variants correlated with mutations detected on commonly mutated genes such as U2AF1 and SF3B1 in patients with AML (supplemental Figure 4).…”

“…6,[8][9][10][11][12][13][14][15][16] For some cancers, these splicing alterations create functionally significant biomarkers. 9,12,14,[17][18][19][20][21] Using exome sequencing, frequent mutations in genes involved in regulating splicing were identified in myelodysplasia (MDS) and in some AML patients. 22 Recently, using a single nucleotide polymorphism (SNP) array and targeted sequencing of 1000 genes, novel somatic mutations of splicing factor SFPQ and splicing regulator CTCF were identified in 10% of AML patients.…”

Very Low PSA Concentrations and Deletions of the KLK3 Gene

“…Alternative splicing (20 ) and intron-retention (21 ) events have been described for KLK3. The results 2 comparisons with frequency data from the dbSNP database and Parikh et al (12 ) combined.…”

Intron Retention: A Common Splicing Event within the Human Kallikrein Gene Family

“…Numerous kallikreins are established or emerging biomarkers for the diagnosis, prognosis, and monitoring of cancer at the mRNA and/or protein level. Splice variants of these genes display cancer-specific expression, or they are differentially expressed in cancer (22)(23)(24)(25)57 ). In this study, we found that the splice variant of the KLK15 gene is up-regulated in 8 of 12 prostate cancer tissues compared with the corresponding healthy tissue samples.…”

“…An exception is one KLK4 isoform, which retains all of the residues of the catalytic triad but lacks the signal peptide and is thought to act intracellularly (21 ). Despite the fact that alternative splicing substantially increases the diversity of this locus, most of these putative protein isoforms have not been isolated, with the exception of a few proteins encoded by KLK2 and KLK3 variants (22 ). The association of some of these splice variants with cancer has been examined (23)(24)(25)(26)(27)(28)(29).…”