Macroautophagy/autophagy maintains cellular homeostasis by degrading cytoplasmic components and its disruption is linked to Parkinson disease (PD), which is characterized by dopamine depletion and the accumulation of SNCA/α-synuclein aggregates in neurons. Therefore, activation of autophagy is considered a therapeutic strategy for PD; however, autophagy inducers have not yet been developed as therapeutic drugs because they are involved in a wide range of signaling pathways. Here, we focused on the lysosomal clustering around the microtubule-organizing center (MTOC) that can regulate the process of autophagosome-lysosome fusion, the final step of autophagy, and examined how lysosomal clustering affects protein degradation through autophagy.
View Article and Find Full Text PDFOsteosarcoma (OS) in humans is characterized by alterations in the TP53 gene. In mice, loss of p53 triggers OS development, for which c-Myc (Myc) oncogenicity is indispensable. However, little is known about which genes are targeted by Myc to promote tumorigenesis.
View Article and Find Full Text PDFThe autophagy-lysosome pathway plays an indispensable role in the protein quality control by degrading abnormal organelles and proteins including α-synuclein (αSyn) associated with the pathogenesis of Parkinson's disease (PD). However, the activation of this pathway is mainly by targeting lysosomal enzymic activity. Here, we focused on the autophagosome-lysosome fusion process around the microtubule-organizing center (MTOC) regulated by lysosomal positioning.
View Article and Find Full Text PDFOsteosarcoma (OS) is characterized by TP53 mutations in humans. In mice, loss of p53 triggers OS development, and osteoprogenitor-specific p53-deleted mice are widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms underlying the initiation or progression of OS following or parallel to p53 inactivation remain largely unknown.
View Article and Find Full Text PDFThe RUNX transcription factors are frequently dysregulated in human cancers, suggesting their potential as attractive targets for drug treatment. However, all three transcription factors have been described as both tumor suppressors and oncogenes, indicating the need to determine their molecular mechanisms of action. Although RUNX3 has long been considered a tumor suppressor in human cancers, several recent studies have shown that RUNX3 is upregulated during the development or progression of various malignant tumors, suggesting it may act as a "conditional" oncogene.
View Article and Find Full Text PDFRetrograde transport of lysosomes is recognised as a critical autophagy regulator. Here, we found that acrolein, an aldehyde that is significantly elevated in Parkinson's disease patient serum, enhances autophagy by promoting lysosomal clustering around the microtubule organising centre via a newly identified JIP4-TRPML1-ALG2 pathway. Phosphorylation of JIP4 at T217 by CaMK2G in response to Ca fluxes tightly regulated this system.
View Article and Find Full Text PDFp53 deficiency and Myc dysregulation are frequently associated with cancer. However, the molecular mechanisms linking these two major oncogenic events are poorly understood. Using an osteosarcoma model caused by p53 loss, we have recently shown that Runx3 aberrantly upregulates Myc via mR1, a Runx consensus site in the Myc promoter.
View Article and Find Full Text PDFCell Death Discov
January 2022
Autophagy plays important role in the intracellular protein quality control system by degrading abnormal organelles and proteins, including large protein complexes such as ribosomes. The eukaryotic chaperonin tailless complex polypeptide 1 (TCP1) ring complex (TRiC), also called chaperonin-containing TCP1 (CCT), is a 1-MDa hetero-oligomer complex comprising 16 subunits that facilitates the folding of ~10% of the cellular proteome that contains actin. However, the quality control mechanism of TRiC remains unclear.
View Article and Find Full Text PDFOsteosarcoma (OS) in human patients is characterized by genetic alteration of TP53. Osteoprogenitor-specific p53-deleted mice (OS mice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown.
View Article and Find Full Text PDFThere exists a close connection between changes occurring in the teeth and those occurring in the jaw during the evolutionary process. In mammals, the roots of teeth are supported, along with periodontal ligaments and alveolar bones by a unique structure termed the gomphosis. In the present study, we performed combined in silico analysis using the information obtained from various DNA microarrays and identified 19 putative tooth root formation-related genes.
View Article and Find Full Text PDFThe RUNX transcription factors serve as master regulators of development and are frequently dysregulated in human cancers. Among the three family members, RUNX3 is the least studied, and has long been considered to be a tumor-suppressor gene in human cancers. This idea is mainly based on the observation that RUNX3 is inactivated by genetic/epigenetic alterations or protein mislocalization during the initiation of tumorigenesis.
View Article and Find Full Text PDFRunx2 and Sp7 are essential transcription factors for osteoblast differentiation. However, the molecular mechanisms responsible for the proliferation of osteoblast progenitors remain unclear. The early onset of Runx2 expression caused limb defects through the Fgfr1-3 regulation by Runx2.
View Article and Find Full Text PDFRunx2 plays important roles in the regulation of chondrocyte differentiation and proliferation; however, the Runx2 target molecules still remain to be investigated. We searched the genes upregulated by the introduction of Runx2 into Runx2(-/-) chondrocytes using microarray and found that Tcf7 is upregulated by Runx2. Thus, we examined the functions of Runx2 in the regulation of the Tcf/Lef family of transcription factors.
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