Abstract A11: Biophysical Characterization of the B-Hlh-lz of Deltamax

Abstract Myc proteins (N-, L- and c-Myc) are transcriptional regulators with a broad spectrum of target genes. While essential for development, cell growth and proliferation as well as apoptosis, they play a major role in cancer onset and progression when deregulated. Myc protein functions depend on their heterodimerization with Max, another transcriptional regulator capable of forming a homodimer and antagonizing c-Myc transcriptional regulation. Recent studies have shown that c-Myc can control the alternative splicing of Max's pre-messenger RNA to produce a c-terminal truncated isoform called deltaMax. The ratio of deltaMax/WT-Max (p21) in cancer cells correlates with increased malignancy. In addition to producing a shorter gene product, the alternative splicing (exon-inclusion) generates a change in sequence in the LZ. The LZ domain is an integral and crucial part of the b-HLH-LZ motif of Max controlling its homodimerization and specific heterodimerization with c-Myc as well as binding to the E-box sequences found in gene promoters and enhancers. Whereas it has been demonstrated that deltaMax increases c-Myc transcriptional activities, the underlying mechanisms have not been elucidated yet. Here, we provide original insights into such mechanisms. First, we show that contrary to the WT motif, the b-HLH-LZ of deltaMax does not homodimerize. In addition, while the b-HLH-LZ of deltaMax can still heterodimerize with the b-HLH-LZ of c-Myc, it can no longer compete with the binding of the heterodimer to E-box sequences. Taken together, our results demonstrate that deltaMax can maximize the amount of c-Myc bound target gene promoters and enhancers and explain how deltaMax and the ratio of deltaMax/WT-Max (p21) in cancer cells can increase c-Myc oncogenic activities. Citation Format: Loïka Maltais, Cynthia Tremblay, Mikaël Bédard, Martin Montagne, Pierre Lavigne. Biophysical characterization of the b-HLH-LZ of deltaMax. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A11.