UCLA

Cell signaling networks govern basic cellular activities including cell growth, proliferation, survival and death. Dysregulation of signaling pathways caused by dysfunctional kinases and hormone receptors is commonly seen in human cancers. Ribosomal protein S6 (rpS6) has been indicated to be involved in determining cell size, cell proliferation and glucose homeostasis. The dissertation work dissected the regulation of S6 phosphorylation (pS6) by growth factor-driven pathways and amino acids in details. It challenged the common notion that pS6 is a good readout for the PI3K/Akt pathway in therapeutic evaluation by showing that pS6 received inputs from and could potentially depend on both overactivated PI3K and MAPK pathways in cancer cells. Furthermore, it provided evidence that a sustained amino acid input to mTORC1 was sufficient to cause pS6 and cell proliferation resistance to Akt and MEK inhibitors, which raised the possibility to target the amino acids/mTORC1 axis in anticancer treatment. The dissertation also comprised a functional study of constitutively active androgen receptor (AR) splice variants in castration resistant prostate cancer (CRPC). By using immunoflurescent staining, luciferase reporter assay and xenograft animal models, we showed that only constitutively nuclear localized AR variants displayed transcriptional activity and growth advantage. However, those variants lost their activity when full length AR was blocked either pharmacologically or genetically, hence were not considered the cause of drug resistance in CRPC.