LRAT (
lecithin:retinol acyltransferase), an
enzyme whose levels are modulated during malignant conversion, has been reported as the founder member of a new LRAT-like family that includes
tumor suppressors TIG-3(1-164) and Ha-Rev107(1-162). The mechanisms that link these three
proteins to
carcinogenesis as well as the significance of a reported shared sequence homologous region remain unclear. This begs the question if the
tumor suppressors possess
enzyme properties and/or if the LRAT
enzyme possesses
tumor suppressor properties. We use the reported homologous region as a first approach to address the question from the perspective that all three
proteins can possess
tumor suppressor properties. We postulated that the homologous sequence harbors an anti-proliferation domain within the full-length
proteins and that dodecapeptides of this sequence possess anti-proliferative activity. We report that H-TIG-3(111-123), H-Ha-Rev107-1(111-123) and H-LRAT160-171:C168L exhibited in vitro growth inhibitory activity in a human cutaneous
melanoma (HCM) model and affected
tumor growth in a nude mouse model. Further, in
peptide-sensitive HCM cells, these
peptides crossed the plasma membrane and localized to the nucleus, where they could bind and activate promoters of
transcription factors involved in G1-->S transition. Moreover,
peptide-induced abrogation of
cyclin dependent kinase-2 expression was concomitant with sub-cellular re-distribution of
cyclins E and A. Indeed, the sequence homologous region within each full-length wild-type
protein as well as the growth inhibitory
peptides can form alpha helices, a likely configuration for binding to
DNA. This is the first report that this sequence homologous region (AA111-123) within these LRAT-like
proteins harbors an anti-proliferative domain with
DNA binding properties. Sequences from this sequence homologous region can be used as templates for anti-
tumor drug design and as probes to investigate disease-related mechanisms and structure-activity relationships of the full-length
proteins, TIG-3(1-164), Ha-Rev107(1-162) and LRAT160-171.