http://web.mit.edu/7.61/restricted/readings/Songyang.pdf

SH2 domains recognize specific phosphopeptide sequences

Oncogenes and signal transduction

Histones are characterized by numerous posttranslational modifications that influence gene transcription. However, because of the lack of global distribution data in higher eukaryotic systems, the extent to which gene-specific combinatorial patterns of histone modifications exist remains to be determined. Here, we report the patterns derived from the analysis of 39 histone modifications in human CD4(+) T cells. Our data indicate that a large number of patterns are associated with promoters and enhancers. In particular, we identify a common modification module consisting of 17 modifications detected at 3,286 promoters. These modifications tend to colocalize in the genome and correlate with each other at an individual nucleosome level. Genes associated with this module tend to have higher expression, and addition of more modifications to this module is associated with further increased expression. Our data suggest that these histone modifications may act cooperatively to prepare chromatin for transcriptional activation.

/pdf/combinatorial-patterns-of-histone-acetylations-and-3tprg69q8k.pdf

Combinatorial patterns of histone acetylations and methylations in the human genome

The effect of mammary gland-specific expression of the polyomavirus middle T antigen was examined by establishing lines of transgenic mice that carry the middle T oncogene under the transcriptional control of the mouse mammary tumor virus promoter/enhancer. By contrast to most transgenic strains carrying activated oncogenes, expression of polyomavirus middle T antigen resulted in the widespread transformation of the mammary epithelium and the rapid production of multifocal mammary adenocarcinomas. Interestingly, the majority of the tumor-bearing transgenic mice developed secondary metastatic tumors in the lung. Taken together, these results suggest that middle T antigen acts as a potent oncogene in the mammary epithelium and that cells that express it possess an enhanced metastatic potential.

/pdf/induction-of-mammary-tumors-by-expression-of-polyomavirus-27zd4ylv1g.pdf

Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease.

Cholesterol and the cell membrane.

Phosphorylation of middle T by pp60c-src: a switch for binding of phosphatidylinositol 3-kinase and optimal tumorigenesis.

Progression from G(1) to S is essential for polyomavirus DNA replication and depends on the interaction of large T with the retinoblastoma gene product pRb. This virus-induced replication pathway is accompanied by p53 activation resembling a DNA damage response (12). We sought to determine whether this pathway depends in part on activation of the ATM (ataxia telangiectasia mutated) kinase and whether the virus gains advantages from this pathway beyond that of entry into S. We show that polyomavirus infection activates the S- and G(2)-phase checkpoints in primary as well as established mouse cells. Infected cells undergo a prolonged S phase compared to uninfected serum-stimulated cells and show no evidence of a G(2)-->M transition before lytic death ensues. Infection is accompanied by increases in ATM activity in vitro and in the level of ATM-S1981-P in vivo. The incubation of infected cells with caffeine, a known ATM inhibitor, did not block entry into S but reduced the rate of viral compared to cellular DNA synthesis. Importantly, caffeine lowered the yields of viral DNA an average of 3- to 6-fold and those of infectious virus by as much as 10-fold. Virus yields were 10-fold lower in ATM (-/-) p53(-/-) than in ATM(+/+) p53(-/-) mouse embryo fibroblasts, indicating a p53-independent role of ATM in productive infection. Replacement of the normal SMC1 (structural maintenance of chromosomes, or cohesin) protein, a critical ATM substrate in the DNA repair pathway, with its phosphorylation mutant SMC1(S957AS966A) also lowered virus yields by roughly 90%. We suggest that polyomavirus activates and utilizes a component(s) of an ATM pathway of DNA repair to prolong S phase and aid its own replication.

Induction and Utilization of an ATM Signaling Pathway by Polyomavirus

The effects of ergosterol, yeast's natural sterol, on cell cycling and a protein kinase antigenically related to pp60v-src were examined in a sterol auxotroph of Saccharomyces cerevisiae. Sterol-depleted cells accumulate in an unbudded, G1 state. Cell budding and proliferation are reinitiated upon addition of nonlimiting ergosterol or cholesterol with trace ergosterol, whereas cholesterol or trace ergosterol alone is less effective. Stimulation of a protein kinase associated with immune complexes of yeast protein and anti-pp60v-src shows a positive correlation with exit from the G1 phase following ergosterol addition. Ergosterol-stimulated cells also demonstrate an increase in phosphatidylinositol kinase activity. The data suggest that hormonal levels of ergosterol (effective concentration, approximately equal to 1 nM) participate in a signaling process associated with a protein kinase possibly involved in yeast cell cycle control.

A protein kinase antigenically related to pp60v-src possibly involved in yeast cell cycle control: positive in vivo regulation by sterol

Sterols in membranes: growth characteristics and membrane properties of Mycoplasma capricolum cultured on cholesterol and lanosterol.

Various alkyl-substituted sterols and stanols representative of the intermediates in cholesterol biosynthesis from lanosterol have been compared with respect to (a) their effect on the physical state of lecithin vesicles, (b) their efficacy as growth factors for the sterol auxotroph Mycoplasma capricolum, and (c) their effect on the physical state of the respective mycoplasma membranes. By all three criteria, sterol effectiveness progresses in the order lanosterol less than 4,4-dimethylcholestanol less than or equal to 4 beta-methylcholestanol less than 4 alpha-methylcholestanol less than cholestanol less than cholesterol. Since the corresponding steps in cholesterol biosynthesis occur in the same order, we conclude that the nuclear modifications of the lanosterol structure by oxidative demethylation serve to improve the membrane function of the sterol molecule.

Jean Dahl

Papers

Phosphorylation of middle T by pp60c-src: a switch for binding of phosphatidylinositol 3-kinase and optimal tumorigenesis.

Induction and Utilization of an ATM Signaling Pathway by Polyomavirus

A protein kinase antigenically related to pp60v-src possibly involved in yeast cell cycle control: positive in vivo regulation by sterol

Sterols in membranes: growth characteristics and membrane properties of Mycoplasma capricolum cultured on cholesterol and lanosterol.

Effect of alkyl-substituted precursors of cholesterol on artificial and natural membranes and on the viability of Mycoplasma capricolum