Our study highlights the overactivated neddylation pathway in lung cancer development and as a promising therapeutic target.

The proproliferative transcription factor KLF5 plays an important role in promoting cell proliferation and tumorigenesis. KLF5 is a short-lived protein that can be rapidly degraded through the ubiquitin-proteasome pathway in cancer cells. However, the mechanisms regulating protein stability remain poorly understood. In this study, the tumor suppressor Fbw7, a component of the SCF complex (SCF Fbw7 ) E3 ubiquitin ligase, specifically promoted the degradation and ubiquitination of KLF5 but had little effect on the stability of KLF4. Fbw7 interacted with KLF5 in a CDC4 phosphodegron (CPD)-dependent manner. Three CPDs were found in the KLF5 protein. Simultaneous mutation of these CPDs significantly abolished Fbw7-mediated ubiquitination and degradation. Furthermore, Fbw7 deficiency dramatically delayed KLF5 turnover and led to the accumulation of KLF5 protein in cancer cells. Glycogen synthase kinase-3␤ could phosphorylate and promote Fbw7-mediated KLF5 degradation. More importantly, Fbw7 negatively regulated the biological activity of KLF5 in gene regulation and cell proliferation. Taken together, these data indicate that Fbw7 is a key negative regulator controlling KLF5-mediated cell proliferation and suggest an additional mechanism linking the loss of Fbw7 function to tumorigenesis. Sp/Krüppel-like factor (KLF) 2 transcription factors are involved in various biological processes and human diseases (1, 2). KLF5 (also known as IKLF and BTEB2) is a basic KLF transcription factor that regulates cell proliferation and plays an important role in diverse physiological and pathological processes, including stemness, inflammation, and atherogenesis (3, 4). As a proproliferative factor, KLF5 also has essential functions in tumorigenesis (3). Increasing evidence indicates that KLF5 can function as an oncogenic protein by promoting cell proliferation in many cancers (5-10). For example, a high expression level of KLF5 correlates with a shorter survival time in breast cancer patients (11). Inhibition of KLF5 expression by pharmacological or genetic methods significantly reduces colorectal cancer cell proliferation (6, 12). However, under certain conditions, KLF5 can also act as a tumor suppressor in some cancers (13,14). The exact mechanisms underlying these apparently contradictory functions are not completely understood.The function of KLF5 is regulated at multiple levels. KLF5 transcription is regulated by several signaling molecules such as Wnt and lysophosphatidic acid (15,16). At the post-translational level, KLF5 function is modulated by phosphorylation, sumoylation, and acetylation (3). Phosphorylation of KLF5 by protein kinase C enhances its transactivation activity and its interaction with CBP (cAMP-responsive element-binding protein-binding protein) (17), whereas sumoylation regulates KLF5-mediated lipid metabolism and its subcellular localization (18,19).KLF5 is an unstable protein with a short half-life in cells. Its protein levels are regulated negatively by the ubiquitin-proteasome pathway (20). The E3 ubiquiti...

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Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure–activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating cardiovascular disease.

Orientation and alignment of molecules by ultrashort laser pulses is crucial for a variety of applications and has long been of interest in physics and chemistry, with the special emphasis on stereodynamics in chemical reactions and molecular orbitals imaging. As compared to the laser-induced molecular alignment, which has been extensively studied and demonstrated, achieving molecular orientation is a much more challenging task, especially in the case of asymmetric-top molecules. Here, we report the experimental demonstration of all-optical field-free three-dimensional orientation of asymmetric-top molecules by means of phase-locked cross-polarized two-color laser pulse. This approach is based on nonlinear optical mixing process caused by the off-diagonal elements of the molecular hyperpolarizability tensor. It is demonstrated on SO2 molecules and is applicable to a variety of complex nonlinear molecules.