Figure 2
(A) Predicted mechanisms of resistance to rapamycin analogues. Rapamaycin or its derivatives (red balls) can be eliminated from cells by ABC transporters such as P-glycoprotein. Mutations of FKBP or mTOR (yellow stars) confer resistance. Acquired resistance to rapamycin has been associated with decreased stoichiometry between 4E-BP and eIF4E, either through decreased translation of 4E-BP or overexpression of eIF4E. (B) Inhibition of mTOR leads to decreased translation of cyclin D1 mRNA, and reduced levels of cyclin D1. In many cells, there is a concomitant stabilisation of the cyclin-dependent kinase inhibitor p27Kip1, and inhibition of CDK-cyclin activity, and decreased phosphorylation of RB. Cells deficient in p27Kip1 are partially resistant, whereas RB-null cells are completely resistant to inhibition of proliferation by rapamycin.
