Proposed model of the elastase-dependent I3C anti-proliferative cascade that targets and requires nucleostemin. (A) In proliferative cells in the absence of I3C, the elastase cleavage of CD40 triggers signaling through TRAF6 that results in activated Akt phosphorylation of MDM2. As a result, MDM2 interacts with both the nuclear and cytoplasmic forms of p53 and thereby prevents the apoptotic activity of this tumor suppressor protein. Under these proliferative conditions, nucleostemin remains in a nucleolus compartment. (B) I3C inhibits the elastase cleavage of CD40 and thereby disrupts the CD40–TRAF6 interaction and inhibits signaling through TRAF6, which results in the loss of MDM2 phosphorylation. The non-phosphorylated MDM2 and phosphorylated MDM2 are sequestered into the nucleolus by their interaction with nucleostemin, which then releases p53 to mediate its apoptotic response. The I3C anti-proliferative cascade is disrupted by expression of an I3C-resistant form of elastase, by the siRNA knockdown of nucleostemin, or by the expression of a dominant negative p53. I3C, indole-3-carbinol; MDM2, murine double mutant 2; NS, nucleostemin; TRAF6, tumor necrosis factor receptor activator factor-6.