Splice Variants of Human Cathepsin L mRNA Show Different Expression Rates

Abstract

Human cathepsin L (hCATL) mRNA occurs in vivo in at least three splice variants. They differ in the length of exon 1, which comprises 278 nucleotides (hCATL-A), 188 nucleotides (hCATL-A2) and 132 nucleotides (hCATL-A3), respectively. We describe here the shortest variant for the first time. This form is predominant in all tissues and cells examined so far, including malignant tumors. We studied the expression rate of the three mRNA variants in order to explain why malignant kidney tumors show low cathepsin L activity despite of high mRNA levels. The variant hCATL-A3 showed the highest expression rate in vitro and in vivo. Based on these results, we suggest a cis-acting element on human cathepsin L mRNA which can be bound by a negative trans-acting regulator, thus leading to reduced expression rates.

Specialized roles for cysteine cathepsins in health and disease

“…done to analyze the promoter regions of the human cathepsin L gene (CTSL) promoter as well as to understand the regulation of different splice variants within the 5′ untranslated region of the transcript (21,22). Of note, one of the splice variants contains a functional internal ribosomal entry site that enables ongoing translation of human cathepsin L under stress conditions, and hypoxia can shut down cap-dependent translation initiation (23).…”

“…30 and 108). The mature proteins are generally small (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and mostly monomeric, with the exception of tetrameric cathepsin C, which contains a C-terminal extension for assembly (109). Posttranslational processing generally results in cleavage of the enzyme into disulfide-linked heavy and light chains (110).…”

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

“…The shorter variants CTSL-A1 (NCBI entry NM_125791.1), CTSL-A2 (described in Ref. 15), and CTSL-A3 (NCBI entry NM_145918.2) are lacking gradually longer parts of the 3Ј part of exon 1. The size of exon 1 in these transcripts is 315 bp for CTSL-A1, 250 bp for CTSL-A2, and 195 bp for CTSL-A3.…”

“…Most of them vary in their length of the 5Ј UTR caused by different splice acceptor sites of exon 1 that are joined to the 5Ј end of exon 2 as depicted in Fig. 3A (14,15). The CTSL open reading frame starts in exon 2 so all splice variants encode for the same functional protein.…”

“…In previous studies contradictory findings about translation efficiencies have been reported. Some reports assign the highest translation efficiency to the shortest variant (15), whereas others state that the longest variant is favored (16). Only some of the previous reports take into account that translation has to be assessed upon conditions that prevail within the cancer tissue.…”