Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms

The tumor suppressor Bin1 nas identified through its interaction with the N -terminal region of Myc which harbors its transcriptional activation domain . Here we show that Bin1 and Myc physically and functionally associate in c ells and that Bin1 inhibits cell proliferation through both Myc-dependent a nd Myc-independent mechanisms. Bin1 specifically inhibited transactivation by Myc as assayed from artificial promoters or from the Myc target genes or nithine decarboxylase (ODC) and alpha prothymosin (pT). Inhibition of ODC b ut not pT required the presence of the Myc binding domain (MBD) of Bin1 sug gesting two mechanisms of action. Consistent with this possibility, a non-M BD region of Bin1 was sufficient to recruit a repression function to DNA th at was unrelated to histone deacetylase. Regions outside the MBD required f or growth inhibition were mapped in Ras cotransformation or HepG2 hepatoma cell growth assays. Bin1 required the N-terminal BAR domain to suppress foc us formation by Myc whereas the C-terminal U1 and SH3 domains were required to inhibit adenovirus E1A or mutant p53, respectively. All three domains c ontributed to Bin1 suppression or tumor cell growth but BAR-C was most cruc ial. These findings supported functional interaction between Myc and Bin1 i n cells and indicated that Bin1 could inhibit malignant cell growth through multiple mechanisms.