Michael S. Cohen

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Converging signals from the mammalian target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K) pathways are well established to modulate translation initiation. Less is known regarding the molecular basis of protein synthesis regulated by other inputs, such as agonists of the Ras/extracellular signal-regulated kinase (ERK) signaling cascade.(More)
The eukaryotic translation initiation factor 4B (eIF4B) plays a critical role in recruiting the 40S ribosomal subunit to the mRNA. In response to insulin, eIF4B is phosphorylated on Ser422 by S6K in a rapamycin-sensitive manner. Here we demonstrate that the p90 ribosomal protein S6 kinase (RSK) phosphorylates eIF4B on the same residue. The relative(More)
Epigenetic gene silencing is seen in several repeat-expansion diseases. In fragile X syndrome, the most common genetic form of mental retardation, a CGG trinucleotide-repeat expansion adjacent to the fragile X mental retardation 1 (FMR1) gene promoter results in its epigenetic silencing. Here, we show that FMR1 silencing is mediated by the FMR1 mRNA. The(More)
Protein phosphorylation is a ubiquitous mechanism for cellular signal propagation, and signaling network complexity presents a challenge to protein kinase substrate identification. Few targets of Polo-like kinases are known, despite their significant role in coordinating cell-cycle progression. Here, we combine chemical-genetic, bioinformatic, and proteomic(More)
BACKGROUND The accuracy of the prostate biopsy Gleason grade to predict the prostatectomy Gleason grade varies tremendously in the literature. OBJECTIVES Determine the accuracy and distribution of the prostate biopsy Gleason grade and prostatectomy Gleason grade at LCMC (Lahey Clinic Medical Center) and worldwide. DESIGN, SETTING, AND PARTICIPANTS(More)
The RAS-stimulated RAF-MEK-ERK pathway confers epithelial cells with critical motile and invasive capacities during development, tissue regeneration, and carcinoma progression, often via promoting the epithelial-mesenchymal transition (EMT). Many mechanisms by which ERK exerts this control remain elusive. We demonstrate that the ERK-activated kinase RSK is(More)
The BimEL tumor suppressor is a potent proapoptotic BH3-only protein. We found that, in response to survival signals, BimEL was rapidly phosphorylated on three serine residues in a conserved degron, facilitating binding and degradation via the F box protein betaTrCP. Phosphorylation of the BimEL degron was executed by Rsk1/2 and promoted by the(More)
In the budding yeast Saccharomyces cerevisiae, the protein phosphatase Cdc14 triggers exit from mitosis by promoting the inactivation of cyclin-dependent kinases (CDKs). Cdc14's activity is controlled by Cfi1/Net1, which holds and inhibits the phosphatase in the nucleolus from G1 until metaphase. During anaphase, two regulatory networks, the Cdc14 Early(More)
The active sites of 491 human protein kinase domains are highly conserved, which makes the design of selective inhibitors a formidable challenge. We used a structural bioinformatics approach to identify two selectivity filters, a threonine and a cysteine, at defined positions in the active site of p90 ribosomal protein S6 kinase (RSK). A fluoromethylketone(More)
OBJECTIVE To determine whether transducible peptides that inhibit the oncoproteins HDM2 and Bcl-2 may selectively kill uveal melanoma and retinoblastoma cells. METHODS Peptides were tested by viability assay, flow cytometry, TUNEL (terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labeling) assay, Western blot analysis, and reverse(More)