Project description:To determine how gene expression varies between fast and slow proliferating cells we developed a CFSE-based method to sort cells by intrapopulation heterogeneity in proliferation rate. We sorted cells by proliferation rate, as well as by the mitochondria dye TMRE, and performed mRNA-seq.
Project description:CDH3 is a single-span transmembrane domain glycoprotein that mediates cell-cell adhesion. It is normally expression in basal cells, luminal epithelial cells and monocytes of lung airway epithelial cells. However, the CDH3 gene is also frequently overexpressed in many cancers. Expression of CDH3 is an indicator of poor prognosis in human breast cancer and a marker for real-time monitoring of resistance to first/second generation EGFR-TKIs. In this present manuscript, we describe that high CDH3 expression is correlated with shorter overall survival of patients in lung adenocarcinomas and low CDH3 expression inhibits cells’ proliferation and migration
Project description:Mueller2015 - Hepatocyte proliferation, T160
phosphorylation of CDK2
This model is described in the article:
T160-phosphorylated CDK2
defines threshold for HGF-dependent proliferation in primary
hepatocytes.
Mueller S, Huard J, Waldow K, Huang
X, D'Alessandro LA, Bohl S, Börner K, Grimm D, Klamt S,
Klingmüller U, Schilling M.
Mol. Syst. Biol. 2015; 11(3): 795
Abstract:
Liver regeneration is a tightly controlled process mainly
achieved by proliferation of usually quiescent hepatocytes. The
specific molecular mechanisms ensuring cell division only in
response to proliferative signals such as hepatocyte growth
factor (HGF) are not fully understood. Here, we combined
quantitative time-resolved analysis of primary mouse hepatocyte
proliferation at the single cell and at the population level
with mathematical modeling. We showed that numerous G1/S
transition components are activated upon hepatocyte isolation
whereas DNA replication only occurs upon additional HGF
stimulation. In response to HGF, Cyclin:CDK complex formation
was increased, p21 rather than p27 was regulated, and Rb
expression was enhanced. Quantification of protein levels at
the restriction point showed an excess of CDK2 over CDK4 and
limiting amounts of the transcription factor E2F-1. Analysis
with our mathematical model revealed that T160 phosphorylation
of CDK2 correlated best with growth factor-dependent
proliferation, which we validated experimentally on both the
population and the single cell level. In conclusion, we
identified CDK2 phosphorylation as a gate-keeping mechanism to
maintain hepatocyte quiescence in the absence of HGF.
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Project description:Using our unique and authentic animal model, the pig, we determined which genes in the normal mammary gland are regulated in response to different combinations of the ovarian hormones estrogen and progesterone and the pituitary hormone prolactin. We surgically removed ovaries from 32 pigs to deplete endogenous estrogen and progesterone, and administered bromocriptine to suppress endogenous prolactin. Pigs were treated with all combinations of estrogen, progesterone and bromocriptine and/or haloperidol (to induce prolactin secretion), in a factorial design. Affymetrix arrays were used to analyze RNA from the mammary glands of these pigs and we found that estrogen, prolactin and the interaction of estrogen*prolactin were the primary regulators of gene expression in the mammary gland. This is in contrast to rodents where progesterone has an important role in ductal elongation and branching. Functional enrichment analyses suggest that estrogen promotes cell division while prolactin stimulates elements of fatty acid metabolism and an inflammatory response (in addition to milk protein genes). These results concur with phenotypic changes where estrogen, prolactin and estrogen*prolactin were the most important regulators of morphological development, cell proliferation and steroid receptor expression. Regression analysis of expression data against the rate of cell proliferation in all 32 pigs identified 1669 genes correlated with proliferation (FDR a=0.01). Regression analysis of expression data against proliferation in the 16 pigs treated with E identified 71 genes correlated with proliferation. 29 genes were common to both lists and also regulated by estrogen, and of these 16 have known functions in the cell cycle while the other 13 have never been associated with estrogen regulated mammary gland growth or cell proliferation. Twenty six of these genes were more highly correlated with proliferation than MKI67 (Ki67).
