Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis.

Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018).

What programs the size of animal cells?

The human body is programmed with definite quantities, magnitudes, and proportions. At the microscopic level, such definite sizes manifest in individual cells - different cell types are characterized by distinct cell sizes whereas cells of the same type are highly uniform in size. How do cells in a population maintain uniformity in cell size, and how are changes in target size programmed? A convergence of recent and historical studies suggest - just as a thermostat maintains room temperature - the size of proliferating animal cells is similarly maintained by homeostatic mechanisms.

Proteomic Characterization of a Candidate Polygenic Driver of Metabolism in Non-small Cell Lung Cancer.

Proteome analysis revealed signatures of co-expressed upregulated metabolism proteins highly conserved between primary and non-small cell lung cancer (NSCLC) patient-derived xenograft tumors (Li et al. 2014, Nat. Communications 5:5469).

Visual barcodes for clonal-multiplexing of live microscopy-based assays.

While multiplexing samples using DNA barcoding revolutionized the pace of biomedical discovery, multiplexing of live imaging-based applications has been limited by the number of fluorescent proteins that can be deconvoluted using common microscopy equipment. To address this limitation, we develop visual barcodes that discriminate the clonal identity of single cells by different fluorescent proteins that are targeted to specific subcellular locations. We demonstrate that deconvolution of these barcodes is highly accurate and robust to many cellular perturbations.

p38-mediated cell growth and survival drive rapid embryonic wound repair.

Embryos repair wounds rapidly, with no inflammation or scarring, in a process that involves polarization of the actomyosin cytoskeleton. Actomyosin polarization results in the assembly of a contractile cable around the wound that drives wound closure. Here, we demonstrate that a contractile actomyosin cable is not sufficient for rapid wound repair in Drosophila embryos.

Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK.

While molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for different cell types. It is increasingly clear that cell size is determined by size checkpoints-mechanisms that restrict the cell cycle progression of cells that are smaller than their target size. Previously, we described a p38 MAPK-dependent cell size checkpoint mechanism whereby p38 is selectively activated and prevents cell cycle progression in cells that are smaller than a given target size.

Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth.

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models.

The Ion Transporter NKCC1 Links Cell Volume to Cell Mass Regulation by Suppressing mTORC1.

mTORC1 regulates cellular growth and is activated by growth factors and by essential amino acids such as Leu. Leu enters cells via the Leu transporter LAT1-4F2hc (LAT1). Here we show that the Na/K/2Cl cotransporter NKCC1 (SLC12A2), a known regulator of cell volume, is present in complex with LAT1.

Postnatal Exocrine Pancreas Growth by Cellular Hypertrophy Correlates with a Shorter Lifespan in Mammals.

Developmental processes in different mammals are thought to share fundamental cellular mechanisms. We report a dramatic increase in cell size during postnatal pancreas development in rodents, accounting for much of the increase in organ size after birth. Hypertrophy of pancreatic acinar cells involves both higher ploidy and increased biosynthesis per genome copy; is maximal adjacent to islets, suggesting endocrine to exocrine communication; and is partly driven by weaning-related processes.

Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity.

Cell size uniformity in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether cellular growth rates depend on cell size, by monitoring how variance in size changes as cells grow. Our data revealed that, twice during the cell cycle, growth rates are selectively increased in small cells and reduced in large cells, ensuring cell size uniformity.

Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length.

Animal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length.

Cell biology. On being the right (cell) size.

Different animal cell types have distinctive and characteristic sizes. How a particular cell size is specified by differentiation programs and physiology remains one of the fundamental unknowns in cell biology. In this Review, we explore the evidence that individual cells autonomously sense and specify their own size.

Dynamics extracted from fixed cells reveal feedback linking cell growth to cell cycle.

Biologists have long been concerned about what constrains variation in cell size, but progress in this field has been slow and stymied by experimental limitations. Here we describe a new method, ergodic rate analysis (ERA), that uses single-cell measurements of fixed steady-state populations to accurately infer the rates of molecular events, including rates of cell growth. ERA exploits the fact that the number of cells in a particular state is related to the average transit time through that state.

Quantitative live cell imaging reveals a gradual shift between DNA repair mechanisms and a maximal use of HR in mid S phase.

DNA double-strand breaks are repaired by two main pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR). The choice between these pathways depends on cell-cycle phase; however the continuous effect of cell cycle on the balance between them is still unclear. We used live cell imaging and fluorescent reporters for 53BP1, Rad52, and cell cycle to quantify the relative contribution of NHEJ and HR at different points of the cell cycle in single cells.

Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation.

Metabolic reprogramming has been proposed to be a hallmark of cancer, yet a systematic characterization of the metabolic pathways active in transformed cells is currently lacking. Using mass spectrometry, we measured the consumption and release (CORE) profiles of 219 metabolites from media across the NCI-60 cancer cell lines, and integrated these data with a preexisting atlas of gene expression. This analysis identified glycine consumption and expression of the mitochondrial glycine biosynthetic pathway as strongly correlated with rates of proliferation across cancer cells.

Spontaneous chiral symmetry breaking in early molecular networks.

Background: An important facet of early biological evolution is the selection of chiral enantiomers for molecules such as amino acids and sugars. The origin of this symmetry breaking is a long-standing question in molecular evolution. Previous models addressing this question include particular kinetic properties such as autocatalysis or negative cross catalysis.

Cell growth and size homeostasis in proliferating animal cells.

A long-standing question in biology is whether there is an intrinsic mechanism for coordinating growth and the cell cycle in metazoan cells. We examined cell size distributions in populations of lymphoblasts and applied a mathematical analysis to calculate how growth rates vary with both cell size and the cell cycle. Our results show that growth rate is size-dependent throughout the cell cycle.

Genetic redundancy: new tricks for old genes.

Many crucial components of signal transduction, developmental, and metabolic pathways have functionally redundant copies. Further, these redundancies show surprising evolutionary stability over prolonged time scales. We propose that redundancies are not just archeological leftovers of ancient gene duplications, but rather that synergy arising from feedback between redundant copies may serve as an information processing element that facilitates signal transduction and the control of gene expression.

Preferential protection of protein interaction network hubs in yeast: evolved functionality of genetic redundancy.

The widely observed dispensability of duplicate genes is typically interpreted to suggest that a proportion of the duplicate pairs are at least partially redundant in their functions, thus allowing for compensatory affects. However, because redundancy is expected to be evolutionarily short lived, there is currently debate on both the proportion of redundant duplicates and their functional importance. Here, we examined these compensatory interactions by relying on a genome wide data analysis, followed by experiments and literature mining in yeast.

The regulatory utilization of genetic redundancy through responsive backup circuits.

Functional redundancies, generated by gene duplications, are highly widespread throughout all known genomes. One consequence of these redundancies is a tremendous increase to the robustness of organisms to mutations and other stresses. Yet, this very robustness also renders redundancy evolutionarily unstable, and it is, thus, predicted to have only a transient lifetime.

Polymer GARD: computer simulation of covalent bond formation in reproducing molecular assemblies.

The basic Graded Autocatalysis Replication Domain (GARD) model consists of a repertoire of small molecules, typically amphiphiles, which join and leave a non-covalent micelle-like assembly. Its replication behavior is due to occasional fission, followed by a homeostatic growth process governed by the assembly's composition. Limitations of the basic GARD model are its small finite molecular repertoire and the lack of a clear path from a 'monomer world' towards polymer-based living entities.

Transcription control reprogramming in genetic backup circuits.

A key question in molecular genetics is why severe mutations often do not result in a detectably abnormal phenotype. This robustness was partially ascribed to redundant paralogs that may provide backup for one another in case of mutation. Mining mutant viability and mRNA expression data in Saccharomyces cerevisiae, we found that backup was provided predominantly by paralogs that are expressed dissimilarly in most growth conditions.

Probability rule for chiral recognition.

Molecular Chirality is of central interest in biological studies because enantiomeric compounds, while indistinguishable by most inanimate systems, show profoundly different properties in biochemical environments. Enantioselective separation methods, based on the differential recognition of two optical isomers by a chiral selector, have been amply documented. Also, great effort has been directed towards a theoretical understanding of the fundamental mechanisms underlying the chiral recognition process.

Test of a statistical model for molecular recognition in biological repertoires.

A chance encounter between members of a random repertoire and a molecular target is characteristic of different biological systems, including the immune and olfactory pathways as well as combinatorial libraries. In such systems, the affinity between the target and members of the repertoire is distributed with a probability function describing the propensity of obtaining a particular affinity value. We have previously proposed a phenomenological receptor affinity distribution (RAD) formalism, which describes this probability function based on simple statistical considerations.