Journal of Molecular Cell Biology

https://academic.oup.com/jmcb

List of Papers (Total 362)

Roles of computational modelling in understanding p53 structure, biology, and its therapeutic targeting

The transcription factor p53 plays pivotal roles in numerous biological processes, including the suppression of tumours. The rich availability of biophysical data aimed at understanding its structure–function relationships since the 1990s has enabled the application of a variety of computational modelling techniques towards the establishment of mechanistic models. Together they...

Drugging in the absence of p53

Inactivation of the p53 gene is a key driver of tumorigenesis in various cancer cohorts and types. The quest for a successful p53-based therapy that holds the promise of treating more than half of the cancer population has culminated in extensive knowledge about the role and function of p53 and led to new proposed innovative strategies against p53-defective cancers. We will...

Small molecule activators of the p53 response

Drugging the p53 pathway has been a goal for both academics and pharmaceutical companies since the designation of p53 as the ‘guardian of the genome’. Through growing understanding of p53 biology, we can see multiple routes for activation of both wild-type p53 function and restoration of mutant p53. In this review, we focus on small molecules that activate wild-type p53 and that...

Functional relationship between p53 and RUNX proteins

RUNX genes belong to a three-membered family of transcription factors, which are well established as master regulators of development. Of them, aberrations in RUNX3 expression are frequently observed in human malignancies primarily due to epigenetic silencing, which is often overlooked. At the G1 phase of the cell cycle, RUNX3 regulates the restriction (R)-point, a mechanism that...

The role of p53 in developmental syndromes

While it is well appreciated that loss of the p53 tumor suppressor protein promotes cancer, growing evidence indicates that increased p53 activity underlies the developmental defects in a wide range of genetic syndromes. The inherited or de novo mutations that cause these syndromes affect diverse cellular processes, such as ribosome biogenesis, DNA repair, and centriole...

Host HDAC4 regulates the antiviral response by inhibiting the phosphorylation of IRF3

Class II HDACs, such as HDAC4, are critical regulators of the immune response in various immune cells; however, its role in innate immunity remains largely unknown. Here, we report that the overexpression of HDAC4 suppresses the production of type I interferons triggered by pattern-recognition receptors (PRRs). HDAC4 repressed the translocation of transcription factor IRF3 to the...

Interleukin-6 secretion is limited by self-signaling in endosomes

Cells producing cytokines often express the receptor for the same cytokine, which makes them prone to autocrine signaling. How cytokine release and signaling are regulated in the same cell is not understood. In this study, we demonstrate that signaling by exogenous and self-synthesized inflammatory cytokine interleukin-6 (IL-6) within endosomal compartments acts as a cellular...

The HDAC3 enzymatic activity regulates skeletal muscle fuel metabolism

Histone deacetylase 3 (HDAC3) is a major HDAC, whose enzymatic activity is targeted by small molecule inhibitors for treating a variety of conditions. However, its enzymatic activity is largely dispensable for its function in embryonic development and hepatic lipid metabolism. HDAC3 plays a pivotal role in regulating muscle fuel metabolism and contractile function. Here, we...

FTO is a transcriptional repressor to auto-regulate its own gene and potentially associated with homeostasis of body weight

Fat mass and obesity-associated (FTO) protein is a ferrous ion (Fe2+)/2-oxoglutarate (2-OG)-dependent demethylase preferentially catalyzing m6A sites in RNA. The FTO gene is highly expressed in the hypothalamus with fluctuation in response to various nutritional conditions, which is believed to be involved in the control of whole body metabolism. However, the underlying mechanism...

ACBD3 is required for FAPP2 transferring glucosylceramide through maintaining the Golgi integrity

Glycosphingolipid (GSL) metabolism is involved in various physiological processes, including all major cell signaling pathways, and its dysregulation is linked to some diseases. The four-phosphate adaptor protein FAPP2-mediated glucosylceramide (GlcCer) transport for complex GSL synthesis has been studied extensively. However, the molecular machinery of FAPP2 as a GlcCer...

Metabolic regulation of T cell development by Sin1–mTORC2 is mediated by pyruvate kinase M2

Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mTORC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sin1, an essential component of mTORC2, in T lineage cells results in severely impaired...

Metastasis-related methyltransferase 1 (Merm1) represses the methyltransferase activity of Dnmt3a and facilitates RNA polymerase I transcriptional elongation

Stimulatory regulators for DNA methyltransferase activity, such as Dnmt3L and some Dnmt3b isoforms, affect DNA methylation patterns, thereby maintaining gene body methylation and maternal methylation imprinting, as well as the methylation landscape of pluripotent cells. Here we show that metastasis-related methyltransferase 1 (Merm1), a protein deleted in individuals with...

Microtubule-bundling protein Spef1 enables mammalian ciliary central apparatus formation

Cilia are cellular protrusions containing nine microtubule (MT) doublets and function to propel cell movement or extracellular liquid flow through beating or sense environmental stimuli through signal transductions. Cilia require the central pair (CP) apparatus, consisting of two CP MTs covered with projections of CP proteins, for planar strokes. How the CP MTs of such ‘9 + 2...

BMP4 facilitates beige fat biogenesis via regulating adipose tissue macrophages

Thermogenic beige fat improves metabolism and prevents obesity. Emerging evidence shows that the activation of M2 macrophages stimulates beige adipogenesis, whereas the activation of M1 macrophages, which play a major role in inflammation, impedes beige adipogenesis. Thus, the identification of factors that regulate adipose tissue macrophages (ATMs) will help clarify the...

EMC10 governs male fertility via maintaining sperm ion balance

Infertility is a severe public health problem worldwide that prevails up to 15% in reproductive-age couples, and male infertility accounts for half of total infertility. Studies on genetically modified animal models have identified lots of genes involved in the pathogenesis of male infertility. The underlying causes, however, remain largely unclear. In this study, we provide...

CDYL1 fosters double-strand break-induced transcription silencing and promotes homology-directed repair

Cells have evolved DNA damage response (DDR) to repair DNA lesions and thus preserving genomic stability and impeding carcinogenesis. DNA damage induction is accompanied by transient transcription repression. Here, we describe a previously unrecognized role of chromodomain Y-like (CDYL1) protein in fortifying double-strand break (DSB)-induced transcription repression and repair...

ZBTB7A governs estrogen receptor alpha expression in breast cancer

ZBTB7A, a member of the POZ/BTB and Krüppel (POK) family of transcription factors, has been shown to have a context-dependent role in cancer development and progression. The role of ZBTB7A in estrogen receptor alpha (ERα)-positive breast cancer is largely unknown. Approximately 70% of breast cancers are classified as ERα-positive. ERα carries out the biological effects of...

TGFβ signaling hyperactivation-induced tumorigenicity during the derivation of neural progenitors from mouse ESCs

Clinical therapies of pluripotent stem cells (PSCs)-based transplantation have been hindered by frequent development of teratomas or tumors in animal models and clinical patients. Therefore, clarifying the mechanism of carcinogenesis in stem cell therapy is of great importance for reducing the risk of tumorigenicity. Here we differentiate Oct4-GFP mouse embryonic stem cells...

Attractor landscape analysis of the cardiac signaling network reveals mechanism-based therapeutic strategies for heart failure

Apoptosis and hypertrophy of cardiomyocytes are the primary causes of heart failure (HF), a global leading cause of death, and are regulated through the complicated intracellular signaling network, limiting the development of effective treatments due to its complexity. To identify effective therapeutic strategies for HF at a system level, we develop a large-scale comprehensive...

LincRNA-1614 coordinates Sox2/PRC2-mediated repression of developmental genes in pluripotency maintenance

Large-intergenic noncoding RNAs (lincRNAs) cooperate with core transcription factors to coordinate the pluripotency network of embryonic stem cells. The mechanisms by which lincRNAs affect chromatin structure and gene transcription remain mostly unknown. Here, we identified that a lincRNA (linc1614), occupied by pluripotency factors at its promoter, was indispensable for both...