Pin1 is a peptidyl-prolyl isomerase which plays a critical role in many diseases including cancer and Alzheimer's disease. The essential role of Pin1 is to affect stability, localization or function of phosphoproteins by catalyzing structural changes. Among the collection of Pin1 substrates, many have been shown to be involved in regulating cell cycle progression. The cell cycle disorder caused by dysregulation of these substrates is believed to be a common phenomenon in cancer. A number of recent studies have revealed possible functions of several important Pin1-binding cell cycle regulators. Investigating the involvement of Pin1 in the cell cycle may assist in the development of future cancer therapeutics. In this review, we summarize current knowledge regarding the network of Pin1 substrates and Pin1 regulators in cell cycle progression. In G1/S progression, cyclin D1, RB, p53, p27, and cyclin E are all well-known cell cycle regulators that are modulated by Pin1. During G2/M transition, our lab has shown that Aurora A suppresses Pin1 activity through phosphorylation at Ser16 and cooperates with hBora to modulate G2/M transition. We conclude that Pin1 may be thought of as a molecular timer which modulates cell cycle progression networks.

WW domain-containing oxidoreductase (WWOX), a putative tumour suppressor, is suggested to be involved in the hyperphosphorylation of Alzheimer's Tau. Tau is a microtubule-associated protein that has an important role in microtubule assembly and stability. Glycogen synthase kinase 3β (GSK3β) has a vital role in Tau hyperphosphorylation at its microtubule-binding domains. Hyperphosphorylated Tau has a low affinity for microtubules, thus disrupting microtubule stability. Bioinformatics analysis indicated that WWOX contains two potential GSK3β-binding FXXXLI/VXRLE motifs. Immunofluorescence, immunoprecipitation and molecular modelling showed that WWOX interacts physically with GSK3β. We demonstrated biochemically that WWOX can bind directly to GSK3β through its short-chain alcohol dehydrogenase/reductase domain. Moreover, the overexpression of WWOX inhibited GSK3β-stimulated S396 and S404 phosphorylation within the microtubule domains of Tau, indicating that WWOX is involved in regulating GSK3β activity in cells. WWOX repressed GSK3β activity, restored the microtubule assembly activity of Tau and promoted neurite outgrowth in SH-SY5Y cells. Conversely, RNAi-mediated knockdown of WWOX in retinoic acid (RA)-differentiated SH-SY5Y cells inhibited neurite outgrowth. These results suggest that WWOX is likely to be involved in regulating GSK3β activity, reducing the level of phosphorylated Tau, and subsequently promoting neurite outgrowth during neuron differentiation. In summary, our data reveal a novel mechanism by which WWOX promotes neuronal differentiation in response to RA.

This work demonstrates two DNA-based logic circuits that behave as a half-adder and a half-subtractor. A half-adder is composed of an AND gate and an XOR gate, whereas a half-subtractor consists of an INH gate and an XOR gate. The proposed designs are inspired by molecular beacons.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been recognized as a therapeutic target for EML4-ALK fusion-positive nonsmall cell lung cancer (NSCLC) treatment using type I kinase inhibitors such as crizotinib to take over the ATP binding site. According to Shaw’s measurements, ALK carrying G1202R mutation shows reduced response to crizotinib (IC₅₀ = 382 nM vs. IC₅₀ = 20 nM for wild-type), whereas L1198F mutant is more responsive (IC₅₀ = 0.4 nM). Interestingly, the double mutant L1198F/G1202R maintains a similar response (IC₅₀ = 31 nM) to the wild-type. Herein we conducted molecular modeling simulations to elucidate the varied crizotinib sensitivities in three mutants carrying L1198F and/or G1202R. Both L1198 and G1202 are near the ATP pocket. Mutation G1202R causes steric hindrance that blocks crizotinib accessibility, which greatly reduces efficacy, whereas mutation L1198F enlarges the binding pocket entrance and hydrophobically interacts with crizotinib to enhance sensitivity. With respect to the double mutant L1198F/G1202R, F1198 indirectly pulls R1202 away from the binding entrance and consequently alleviates the steric obstacle introduced by R1202. These results demonstrated how the mutated residues tune the crizotinib response and may assist kinase inhibitor development especially for ALK G1202R, analogous to the ROS1 G2302R and MET G1163R mutations that are also resistant to crizotinib treatment in NSCLC.