Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.

Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease.

FAM122A ensures cell cycle interphase progression and checkpoint control by inhibiting B55α/PP2A through helical motifs.

The Ser/Thr protein phosphatase 2 A (PP2A) regulates the dephosphorylation of many phosphoproteins. Substrate recognition are mediated by B regulatory subunits. Here, we report the identification of a substrate conserved motif [RK]-V-x-x-[VI]-R in FAM122A, an inhibitor of B55α/PP2A.

TRIM33 Is a Co-Regulator of Estrogen Receptor Alpha.

Estrogen receptor alpha (ER)-positive breast cancer is responsible for over 60% of breast cancer cases in the U.S. Among patients diagnosed with early-stage ER+ disease, 1/3 will experience recurrence despite treatment with adjuvant endocrine therapy.

FAM122A ensures cell cycle interphase progression and checkpoint control as a SLiM-dependent substrate-competitive inhibitor to the B55⍺/PP2A phosphatase.

The Ser/Thr protein phosphatase 2A (PP2A) is a highly conserved collection of heterotrimeric holoenzymes responsible for the dephosphorylation of many regulated phosphoproteins. Substrate recognition and the integration of regulatory cues are mediated by B regulatory subunits that are complexed to the catalytic subunit (C) by a scaffold protein (A). PP2A/B55 substrate recruitment was thought to be mediated by charge-charge interactions between the surface of B55α and its substrates.

Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation.

The family of Phosphoprotein Phosphatases (PPPs) is responsible for most cellular serine and threonine dephosphorylation. PPPs achieve substrate specificity and selectivity by forming multimeric holoenzymes. PPP holoenzyme assembly is tightly controlled, and changes in the cellular repertoire of PPPs are linked to human disease, including cancer and neurodegeneration.

A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination.

Mutations in the tumour suppressor gene BRCA2 are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in maintaining genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination (HR). BRCA2 acts by controlling RAD51 nucleoprotein filament formation on resected single-stranded DNA, but how BRCA2 activity is regulated during HR is not fully understood.

A disorder-related variant (E420K) of a PP2A-regulatory subunit (PPP2R5D) causes constitutively active AKT-mTOR signaling and uncoordinated cell growth.

Functional genomic approaches have facilitated the discovery of rare genetic disorders and improved efforts to decipher their underlying etiology. PPP2R5D-related disorder is an early childhood onset condition characterized by intellectual disability, hypotonia, autism-spectrum disorder, macrocephaly, and dysmorphic features. The disorder is caused by de novo single nucleotide changes in PPP2R5D, which generate heterozygous dominant missense variants.

Quantitative kinase and phosphatase profiling reveal that CDK1 phosphorylates PP2Ac to promote mitotic entry.

The reciprocal regulation of phosphoprotein phosphatases (PPPs) by protein kinases is essential to cell cycle progression and control, particularly during mitosis for which the role of kinases has been extensively studied. PPPs perform much of the serine/threonine dephosphorylation in eukaryotic cells and achieve substrate selectivity and specificity through the interaction of distinct regulatory subunits with conserved catalytic subunits in holoenzyme complexes. Using a mass spectrometry-based chemical proteomics approach to enrich, identify, and quantify endogenous PPP holoenzyme complexes combined with kinase profiling, we investigated the phosphorylation-dependent regulation of PPP holoenzymes in mitotic cells.

Fission yeast Pak1 phosphorylates anillin-like Mid1 for spatial control of cytokinesis.

Protein kinases direct polarized growth by regulating the cytoskeleton in time and space and could play similar roles in cell division. We found that the Cdc42-activated polarity kinase Pak1 colocalizes with the assembling contractile actomyosin ring (CAR) and remains at the division site during septation. Mutations in pak1 led to defects in CAR assembly and genetic interactions with cytokinesis mutants.

Methylmercury promotes breast cancer cell proliferation.

Context: Metalloestrogens are small ionic metals that activate the estrogen receptor (ER). Studies have shown that when metalloestrogens bind to the ER, there is an increase in transcription and expression of estrogen-regulated genes, which induces proliferation of estrogen-dependent breast cancer. Methylmercury (MeHg), a metalloestrogen, is present in the environment and is toxic at moderate to high concentrations.

The effect of heat- and auto-polymerized denture base polymers on clonogenicity, apoptosis, and necrosis in fibroblasts: denture base polymers induce apoptosis and necrosis.

Eluates from poly(methyl methacrylate)-based denture base polymers have recently been found to enhance death by apoptosis and necrosis in U-937 human monoblastoid cells. The present study investigated the potential of such polymers to induce apoptosis and/or necrosis and to alter clonogenicity in L929 murine fibroblasts. A fibroblast cell line was chosen because the impairment of fibroblasts subjacent to denture bases may result in a weaker or more permeable mucosa.

Patterns of cell death induced by eluates from denture base acrylic resins in U-937 human monoblastoid cells.

The purpose of this study was to investigate in vitro the apoptosis- and necrosis-inducing potential of eluates from three heat-polymerized and four autopolymerized poly(methyl methacrylate)-based denture base resins. Our hypothesis was that the rate of cell death by apoptosis and/or necrosis induced by such denture base resins could be an important indicator of their cytotoxicity degree. U-937 human monoblastoid cells were exposed for 24 h and 48 h to eluates of 0.

cAMP inhibits translation by inducing Ca2+/calmodulin-independent elongation factor 2 kinase activity in IPC-81 cells.

Treatment of IPC-81 cells led to inhibition of protein synthesis, which was accompanied by an increase in the average size of polysomes and a decreased rate of elongation, indicating that it involved inhibition of peptide chain elongation. This inhibition was also associated with increased phosphorylation of elongation factor eEF2 (which inhibits its activity) and enhanced Ca2+/calmodulin-independent activity of eEF2 kinase. Previous work has shown that phosphorylation of eEF2 kinase by cAMP-dependent protein kinase (cAPK) in vitro induces such activator-independent activity, and the present data show that such a mechanism can occur in intact cells to link physiological levels of cAPK activation with inhibition of protein synthesis.

Multiple apoptotic death types triggered through activation of separate pathways by cAMP and inhibitors of protein phosphatases in one (IPC leukemia) cell line.

The protein phosphatase inhibitors okadaic acid and calyculin A at moderate concentrations induced three types of apoptotic promyelocytic leukemia cell death, distinct with respect to ultrastructure and polynucleotide fragmentation. Calyculin A at higher concentrations (> 50 nM) induced a non-apoptotic death type with high ATP and pronounced micromitochondriosis. This suggests that protein phosphorylation pathways are involved in the triggering of several death pathways.

Cleaved intracellular plasminogen activator inhibitor 2 in human myeloleukaemia cells is a marker of apoptosis.

The proteolytic modification of plasminogen activator inhibitor 2 (PAI-2) was studied during apoptosis in the human promyelocytic leukaemic NB4 cell line during treatment with the phosphatase inhibitors okadaic acid and calyculin A as well as the protein synthesis inhibitor cycloheximide. The apoptic type of cell death was ascertained by morphological and biochemical criteria. In cell homogenates PAI-2 was probed by [125I]urokinase plasminogen activator (uPA) and detected as a sodium dodecyl sulphate-stable M(r) 80,000 complex after reducing sodium dodecyl sulphate-polyacrylamide gel electrophoresis and autoradiography.

Organ culture of a glioblastoma from a patient with an unusually long survival.

Multicellular tumor spheroids were directly initiated in vitro from the biopsy specimens of a patient who is alive and who has had no neurological changes in 7 years after the gross removal of a glioblastoma. The spheroids were studied alone and in confrontation with aggregates of fetal rat brain tissue. Both in the biopsy and in the tumor spheroids, a very high proportion of cells were proliferating, as flow cytometric deoxyribonucleic acid measurements showed that 40% of the cells in the biopsy specimens and in the tumor spheroids were in the S and G2M phases of the cell cycle.