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Figure 2 Schematic illustration of the cell cycle and its regulatory mechanisms that are relevant for the inhibitory effect imposed by sirolimus (SRL) and paclitaxel (PTX). The cell cycle is regulated by the oscillating activities of cyclin/cyclin-dependent kinase (CDK) complexes. Cyclin-dependent kinase inhibitors (CKIs) negatively control the activity of distinct cyclin/CDK complexes. The CKIs of the Cip/Kip class are major regulators of the cell cycle in its initial stage, the G1/S phase. Cip/Kip CKI include p21Cip1 and p27Kip1, among others. Both are critical cell cycle regulators in smooth muscle cells. p27Kip1 activity is regulated at the post-transcriptional level via protein stability and translation. Subsequent to binding its intracellular receptor FKBP12 (FK506 binding protein), SRL inhibits the activity of mammalian target of rapamycin (mTOR). mTOR is a pivotal protein kinase that mediates mitogen-induced cell proliferation. The inhibition of mTOR by SRL attenuates p27Kip1 degradation, thus increasing p27Kip1 protein stability. Additionally, p27Kip1 protein translation may also be enhanced. Non p27Kip1-dependent mechanisms of mTOR that lead to stimulation of cap-dependent protein synthesis and are inhibited by SRL include p70S6K and eIF4E activation, the latter via induction of eIF4E binding protein-1 (4EBP1). Paclitaxel impacts predominantly during cell division in the mitosis (M) phase of the cell cycle through centrosomal impairment, induction of abnormal spindles and suppression of spindle microtubule dynamics.
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