Table 1 List of contextual determinants of nucleocytoplasmic shuttling with determination of opposite cancerous functions of cargos
Molecular determinant | Shuttling protein | Nuclear function of shuttling protein | Mechanisms of nuclear shuttling protein | Cytoplasmic function of shuttling protein | Mechanisms of cytoplasmic shuttling protein | Potential inhibitor | Biomarker |
|---|---|---|---|---|---|---|---|
PSPC1 [27] | PTK6 | PTK6 is a tumor suppressor | PTK6 is phosphorylated and trapped by PSPC1 | PTK6 is an oncogene | PTK6 interacts with proteins in oncogene networks | PSPC1-CT131 | Decreased PSPC1-pY523 expression predicts HCC tumor progression |
TGIF1 | PML | PML is a tumor suppressor | TGIF1 sequesters cPML and acts as a negative TGF-β signal regulator | Cytoplasmic PML (cPML) is an oncogene | cPML is exported into the cytoplasm to interact with Smads for activating TGF-β pathway | Arsenic trioxide (ATO) or All-trans-retinoic acid (ATRA) | PML–RARα fusion oncogene in acute promyelocytic leukemia (APL) |
NPM | HEXIM1 | HEXIM1 is a tumor suppressor | P-TEFb sequesters HEXIM1, resulting in the inactivation of P-TEFb-mediated inhibition of RNA polymerase II transcription | Cytoplasmic NPM mutant (NPMc+) is an oncogene | NPMc + associates with and sequesters HEXIM1, leading to higher RNA polymerase II transcription | Cytotoxic peptide of the basic region (BR) of HEXIM1 | NPMc + is the signature for acute myeloid leukemia (AML) |
Mortalin | P53 | P53 is a tumor suppressor | P53 acts as a suppressor to participate in DNA repair, apoptosis, and cell cycle progression | P53 accumulation and retention in the cytoplasm lead to drug resistance and oncogenic features | Cytoplasmic p53 is sequestered by mortalin due to p53 excessive nuclear export, low cytoplasmic degradation, and retention by the cytoskeleton. | P53 peptide (323–337 amino acids), MKT-077, shRNAs of mortalin | Cytoplasmic p53 is associated with poor chemotherapy, metastasis, and poor patient survival |
EBP50 | EBP50, β-catenin | EBP50 is an oncogene | EBP50/β-catenin enters the nucleus to stabilize β-catenin/TCF-1 to activate aberrant Wnt signaling | EBP50 is a tumor suppressor | EBP50 interacts with the PTEN tumor suppressor to attenuate PDGF receptor signaling | siEBP50 | Nuclear expression of EBP50 is associated with poor survival |