Functional studies on the multidrug transporter ABCB5: a pleiotropic phenotype in knock-out mice

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	CANCER-10

Authors

• J-P Gillet
• W Vieira
• L Tessarollo
• MM Gottesman

Abstract

Recent studies suggest that the expression of ATP-binding cassette B5 (ABCB5) protein is linked to development of multidrug resistance in melanoma. However, these studies were based on the expression of two transcript variants of ABCB5 gene (ABCB5 alpha and ABCB5 beta), which encode truncated ABCB5 proteins. ABCB5 is a very close homolog of the best studied multidrug transporter ABCB1(P-glycoprotein) (78% similarity, 54% identity). Characterizing it as well as understanding its regulation may reveal novel targets for the treatment of intractable melanoma. We found that a third transcript, ABCB5-full-length (ABCB5FL), encoding a full-length functional transporter, is expressed in the melanoma lines in which both ABCB5 alpha and beta transcript variants were detected. High-throughput sequencing performed on both mRNA and total RNA depleted of ribosomal RNAs, supports this finding. To determine the physiological role of ABCB5, we have targeted ABCB5FL in mice. Knock-out mice do not express any of the splice variants and are viable and fertile, but grow more slowly then wild-type mice. Phenotyping revealed altered bioenergetics (decreased lactate and increased O2 consumption). Decreased liver weight and increased heart weight were also observed in knockout males. These results suggest a role in intermediary metabolism for ABCB5.

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