The index below is a selection of new studies and review articles by researchers from across the HMS community. It represents a small sample of research at HMS.
Global Identification of Modular Cullin-RING Ligase Substrates
Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, Yen HC, Elledge SJ. Division of Genetics, Brigham and Women’s Hospital; Department of Genetics, Harvard Medical School; Howard Hughes Medical Institute.
Cullin-RING ligases (CRLs) represent the largest E3 ubiquitin ligase family in eukaryotes, and the identification of their substrates is critical to understanding regulation of the proteome. Using genetic and pharmacologic Cullin inactivation coupled with genetic and proteomic assays, the authors have identified hundreds of proteins whose stabilities or ubiquitylation status are regulated by CRLs. Findings demonstrate the broad role of CRL ubiquitylation in all aspects of cellular biology and provides a set of proteins likely to be key indicators of cellular physiology. Cell. 2011 Oct. 14;147-2:459-474.
Antidiabetic Actions of a Non-agonist PPARγ Ligand Blocking Cdk5-mediated Phosphorylation
Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, Kuruvilla DS, Shin Y, He Y, Bruning JB, Marciano DP, Cameron MD, Laznik D, Jurczak MJ, Schürer SC, Vidović D, Shulman GI, Spiegelman BM, Griffin PR. Dana-Farber Cancer Institute and Department of Cell Biology, HMS.
PPARγ is the functioning receptor for the thiazolidinedione class of antidiabetes drugs. These drugs are full classical agonists, but many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5. The authors describe novel compounds that completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation. One such compound has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Nature. 2011 Sept. 4;477(7365):477-81.
Alcohol Consumption at Midlife and Successful Ageing in Women: A prospective cohort analysis in the nurses’ health study
Sun Q, Townsend MK, Okereke OI, Rimm EB, Hu FB, Stampfer MJ, Grodstein F. Department of Nutrition, Harvard School of Public Health.
Observational studies have documented inverse associations between moderate alcohol consumption and risk of premature death. It is largely unknown whether moderate alcohol intake is also associated with overall health and well-being among populations who have survived to older age. The authors prospectively examined alcohol use assessed at midlife in relation to successful ageing in a cohort of US women. Data suggest that regular, moderate consumption of alcohol at midlife may be related to a modest increase in overall health status among women who survive to older ages. PLoS Medicine. 2011 Sept.;8(9):e1001090.