Figure 9.

Schematic illustration of the proposed mechanism by which NO inhibits RASMC proliferation. NO and DFMO inhibit (|—) ODC and reduce (↓) polyamine synthesis. Polyamine depletion results in the activation (↑) of MEK1/2 and consequent activation of MAPK via phosphorylation. The inactive (i) MAPK is converted to the active (a) phosphorylated (p) MAPK. Addition of exogenous putrescine can prevent (|—) activation of MEK 1/2 by polyamine depletion. U0126 and PD 098,059 (MEK 1/2 inhibitors) block (|—) activation of MAPK. MAPK activation causes up-regulation (↑) of p21^waf1/cip1 and consequent inhibition (↓) of certain cdks, thereby leading to interference with cell cycle progression (blocks G₁ to S-phase transition) and inhibition (↓) of RASMC proliferation.