It exerts oncogenic functions through properties such as hyperactivation of CDK2 due to more stable LMW cyclin E/CDK2 complex formation [169], the resistance of LMW cyclin E/CDK2 complex to inhibitors p21 and p27 [170], altered substrate interactions [171], and cytoplasmic novel interactions that differ from the full-length cyclin E [172]

It exerts oncogenic functions through properties such as hyperactivation of CDK2 due to more stable LMW cyclin E/CDK2 complex formation [169], the resistance of LMW cyclin E/CDK2 complex to inhibitors p21 and p27 [170], altered substrate interactions [171], and cytoplasmic novel interactions that differ from the full-length cyclin E [172]. brain through the extracellular microenvironment. Finally, we shed light on the therapeutic perspectives for the treatment of both cancer and neurodegenerative disorders. ((((((((isomerase (PPIase) NIMA (Never in Mitosis A)-interacting 1 (Pin1), and protein phosphatase 2A (PP2A) (Fig.?2). In Tpo addition, we describe the ST3932 inter-dependent regulation of brain cancers and neurodegeneration through intercellular communications between tumor and neuronal cells in the brain. Furthermore, this review provides some perspectives into the application towards pharmacological therapeutics for both cancer and neurodegenerative diseases. Open in a separate window Fig. 2 Changes in overlapping molecules in cancer and neurodegenerative diseases. Cyclin D and cyclin E are upregulated whereas protein phosphatase 2A (PP2A) is downregulated in both diseases. p53 is downregulated in ST3932 cancer but inversely upregulated in neurodegenerative diseases. Peptidyl-prolyl isomerase NIMA-interacting 1 (Pin1) is mainly upregulated in cancer and Parkinsons disease (PD) but downregulated in Alzheimers disease (AD). Cyclin F is downregulated in cancer, while its mutant form is found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). never in mitosis A Overlapping molecules between cancer and neurodegenerative diseases p53 The transcription factor p53 is an extensively studied tumor suppressor [33C35], and is known to be associated with around 50% of all human malignancies. In most of these cases, p53 gene has been reported to contain missense mutations [36C39]. The mutant p53 proteins no longer have tumor suppressor activity, and obtain several gain-of-functions such as invasion [40C48], enhanced migration [42, 49C52], anchorage-independent growth [53C58], propagation of cell cycle [59C65], cell survival and avoidance of cell death [66C76], genomic instability [77C82], and angiogenesis [83C85]. A commonly occurring mutant form of p53, p53-R273H, contributes to the impaired detoxification of reactive oxygen species (ROS) by decreasing the nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2)-mediated expression of phase 2 ROS-detoxifying enzymes, quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), which resulted in a reduced antioxidant response and imbalance of redox homeostasis in lung or colon cancer cells [70, 86, 87] (Fig.?3). Overexpression of another mutant, p53-G245D, upregulated a transcription factor called forkhead box protein M1 (FOXM1), which exerted oncogenic properties [88]. However, another study showed that the enhanced level of FOXM1 downregulates ROS levels by increasing antioxidant enzymes like superoxide dismutase (SOD) and thioredoxin-dependent peroxide reductase, peroxiredoxin 3 (PRDX3) [89]. These complicated results of mutant p53 on redox homeostasis could warrant more careful considerations when targeting dual factors p53 and redox regulation for the treatment of cancers. Furthermore, mutant p53 proteins ST3932 are rather reluctant to degradation compared to wild-type p53 proteins, and thus the accumulated mutant p53 proteins are often a major therapeutic target for cancer treatment [36, 37, 85, 90C92]. Open in a separate window Fig. 3 Mechanisms of overlapping molecules in cancer and neurodegenerative diseases. (Down) Mutant p53 inhibits the nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2)-mediated antioxidant enzymes, and thus induces reactive oxygen species (ROS) production. Low-molecular-weight (LMW) cyclin E cannot translocate into the nucleus, and forms LMW cyclin E cyclin-dependent kinase 2 (CDK2) complex in the cytoplasm, thereby activating oncogenic functions, such as tumor cell invasion and metastasis. (Top left) Amyloid- (A), A fibrils and plaques are formed from amyloid precursor protein (APP) via amyloidogenic processing. Cyclin D1 promotes tau phosphorylation and induces apoptosis through a caspase 3-mediated pathway. PP2A dephosphorylates phosphorylated tau, and glycogen synthase kinase 3 beta (GSK3) phosphorylates tau. Reduced activity of superoxide dismutase (SOD) and glutathione reductase (GR) induces the increase of ROS production, which leads to the conformational change of p53, and this unfolded p53 is also observed in AD. (Top right) Mutant and glutamate excitotoxicity increase cyclin E accumulation, which induces apoptosis. In addition, p53 also induces the upregulation of apoptotic proteins, such as Bcl-2 associated X (Bax) and caspases 3, which is observed in the PD brain. The interaction between Pin1 and synphilin-1 (an -synuclein-binding protein) enhances the formation of -synuclein inclusions, and this -synuclein inclusion formation can be inhibited by PP2A. endoplasmic reticulum, heme oxygenase-1, quinone oxidoreductase 1, plasma membrane. Molecule name marked in purple indicates studies that involve exogenous proteins Unlike the role of p53 in cancer, the level and activity of p53 in neurodegenerative diseases have been shown to be substantially increased [93C95]. Brains of AD patients and model mice showed increased levels of p53 [96C99] and apoptotic neuronal cell death [100C102]. In double transgenic AD mice that express the mutants of amyloid precursor protein/presenilin (APP/PS) and accumulate.