Figure 7

Schematic drawing of the four upstream molecular signaling pathways of p27 expression that could lead to activation of the unusually long 5'-untranslated region (5'-UTR) (-575) of p27 mRNA by 4-hydroxytamoxifen, dexamethasone and retinoic acids. (a) The two upstream molecular signaling pathways of p27 shown in Figure 5a are pathways #1 and #2. The pathway #1 consisted of receptor tyrosine kinases/phosphoinositide 3-kinase/Akt/tuberous sclerosis complex/mammalian target of rapamycin/eukaryotic translation initiation factor 4E (eIF4E) -binding protein 1 (RTKs/PI3K/Akt/TSC/mTOR/4E-BP1). The pathway #2 consisted of 5'-AMP-activated protein kinase (metabolic energy sensor or cellular fuel gauge)/tuberous sclerosis complex/mammalian target of rapamycin/eIF4E-binding protein 1 (AMPK/TSC/mTOR/4E-BP1). (b) In addition to these two pathways, two more upstream molecular signaling pathways of p27 expression were previously identified. They were pathways #3 and #4. The pathway #3 consisted of receptor tyrosine kinases/MAPKs/eIF4E (RTKs/MAPKs/eIF4E). The pathway #4 consisted of global hypomethylation of the 5'-7-methylguanosine (m⁷G) cap of mRNAs. The specific inhibitors and activators used previously to identify these four pathways are indicated next to each of the four pathways. The results of this study suggested that 4-hydroxytamoxifen used pathway #1 and dexamethasone primarily used pathway #2 to up-regulate the expression of p27. Dexamethasone could also use a portion of pathway #1 secondarily. We also believe, but could not conclude, that 4-hydroxytamoxifen up-regulated the expression of p27 using MAP kinase pathways (Pathway #3 in Figures 5b and 7b). Retinoic acids up-regulated p27 expression without using pathways #1, #2 and #3. We propose a hypothesis that retinoic acids are likely to have used pathway #4 to up-regulate the expression of p27. Abbreviations: see the legend of Figure 5.