Journal Article

Evidence that sequence homologous region in LRAT-like proteins possesses anti-proliferative activity and DNA binding properties: translational implications and mechanism of action

Denise Perry Simmons, Megan L. Peach, Jonathan R. Friedman, Michael M.B. Green, Marc C. Nicklaus and Luigi M. De Luca

in Carcinogenesis

Volume 27, issue 4, pages 693-707
Published in print April 2006 | ISSN: 0143-3334
Published online October 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi235
Evidence that sequence homologous region in LRAT-like proteins possesses anti-proliferative activity and DNA binding properties: translational implications and mechanism of action

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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-31–164 and Ha-Rev1071-162. 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-3111–123, H-Ha-Rev107-1111–123 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-31–164, Ha-Rev1071–162 and LRAT160–171.

Keywords: cdk2, cyclin dependent kinase-2; EMSA, Electrphoretic mobility shift assay; FACS, fluorescence activated cell sorter GIP, growth inhibitory peptide; HMG A1, high mobility group protein; LMW, lower molecular weight; LRAT, Lecithin:retinol acyltransferase; RAR, retinoic acid receptor; RAREs, RAR elements; TGFβ-1, transforming growth factor beta-1

Journal Article.  9857 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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