Molecular Medicine Israel

Most highly ranked articles: 2011(up to June), Cancer & Immunology

Top 7 in Cancer Biology A snapshot of the most highly ranked articles in cancer biology and related areas

1. The genome shuffle
P.J. Stephens, et al., “Massive genomic rearrangement acquired in a single catastrophic event during cancer development,” Cell, 144:27-40, 2011.

In some cancers, chromosomes are broken apart and stitched back together, resulting in tens to hundreds of spontaneous genomic rearrangements, contravening the model of slowly accumulating point mutations and more subtle chromosome rearrangements. The process, dubbed “chromothripsis,” occurs in at least 2-3 percent of all cancers, across many subtypes, and is present in 25 percent of bone cancers.
Newt lung cells in early anaphaseNational Institutes of Health

Newt lung cells in early anaphaseNational Institutes of Health

2. Chromosome segregation key
K.E. Gascoigne KE, et al., “Induced ectopic kinetochore assembly bypasses the requirement for CENP-A nucleosomes,”Cell, 145:410-22, 2011.

Getting chromosome segregation right during mitosis is crucial to accurate cell division, and this delicate orchestration depends on the proper formation and localization of the kinetochore, a protein complex normally formed in the cell’s centromere. New research shows that two DNA-binding proteins, CENP-C and CENP-T, known to drive vertebrate kinetochore formation can direct its assembly even outside the centromere.
3. Endocrine resistant breast cancer
X. Pan, et al., “Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer,” Nat Med., 17:708-14, 2011.

Hormone treatment is a core therapy for breast cancer, but many patients are resistant to the drugs, which target estrogen receptor-α. A ubiquitin-binding protein called CUEDC2 seems to be central to conferring resistance to endocrine drugs like tamoxifen.
4. A cancer protein’s partners
S. Jirawatnotai, et al., “A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers,” Nature, 474:230-4, 2011.

The DNA repair protein cyclin D1 is a hallmark of many cancers, and now an interactome analysis of several tumor types is revealing its function by bringing to light many of its molecular binding partners, such as the recombinase RAD51.
5. The evolution of a replication factor
L. Sanchez-Pulido and C.P. Ponting, “Cdc45: The Missing RecJ Ortholog in Eukaryotes?” Bioinformatics, Jun 8. [Epub ahead of print], 2011.
The protein Cdc45 plays a key role in eukaryotic DNA replication, but its precise enzymatic activity has remained a mystery. Using a bioinformatic approach, researchers determine that Cdc45 is related to the prokaryotic homologous recombination and mismatch repair protein RecJ, suggesting Cdc45 may have a similar function.
6. Cyclin-dependent dynamics revealed
M. Kõivomägi et al., “Dynamics of Cdk1 Substrate Specificity during the Cell Cycle,” Mol. Cell, 42:610-23, 2011.
An important cell cycle regulator called cyclin-dependent kinase 1 (Cdk1) interacts with many different types of cyclin, and now it appears that it’s able to order specific events in the cell cycle by changing its substrate specificity to associate with different cyclins.
7. Longer chromosomes, more compaction
G. Neurohr, et al., “A midzone-based ruler adjusts chromosome compaction to anaphase spindle length,” Science, 332:465-8, 2011.

Cells are able to sense the degree to which they need to condense chromatin during mitosis so that DNA segregates properly between daughter cells. When the longest chromosomes in yeast cells were made 45 percent longer, greater compaction occurred in anaphase to compensate and cells remained viable.

Top 6 in immunology

A snapshot of the most highly ranked articles in immunology and related areas.

1. Receptor-snatching
O.S. Qureshi et al., “Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4,”Science, 332:600-3, 2011. Evaluated by Lieping Chen, Yale Univ Sch of Med; Amnon Altman, La Jolla Inst for Allergy and Immunology; Oberdan Leo and Muriel Moser, U of Brussels, Belgium

In addition to binding the CD80 and CD86 receptors on the surface of antigen presenting cells, impairing their ability to activate T cells, the CTLA-4 receptor on T helper cells can physically snatch away the receptors, demonstrating another mechanism by which this molecule may suppress immunity.
Ulcerative colitisWikimedia Commons

Ulcerative colitisWikimedia Commons

2. TRIMming retroviral infections
T. Pertel et al., “TRIM5 is an innate immune sensor for the retrovirus capsid lattice,” Nature, 472:361-5, 2011. Evaluated by Qian Yin and Hao Wu, Weill Med Coll, Cornell Univ; Gijs Versteeg and Adolfo Garcia-Sastre, Mount Sinai School of Med; Vojo Deretic, Univ New Mexico.

TRIM5, a ubiquitin ligase that helps thwart retroviral infections, works by promoting innate immune signaling and acting as a pattern recognition receptor that binds the retrovirus capsid lattice, adding to a growing list of TRIMs that regulate innate immune responses.
3. Linking genes and bacteria in colitis
E. Elinav et al., “NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis,” Cell, 145:745-57, 2011. Evaluated by Lisa Maier and Wolf-Dietrich Hardt, Swiss Federal Inst of Tech (ETH), Switzerland; Peter Murray, St. Jude Children’s Res Hosp;  Kim Newton and Vishva Dixit, Genentech.
Mice that lack a gene for a key component of the immune system are more susceptible to colitis, and develop a gut-microbe enriched in one type bacteria. Furthermore, when mice that had a functional copy of the innate component are housed with knockout mice lacking the gene, both groups are susceptible to colitis, suggesting that gut microbial composition of the knockout mice spreads to the wild-type, and that both genes and microbes are involved in this autoimmune disease.
4. Regulation of autoimmune factor revealed
X.P. Yang et al., “Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5,” Nat Immunol, 12:247-54, 2011. Evaluated by Allen Ho, Abhishek V. Garg and Sarah Gaffen, Univ of Pittsburgh; Patrick Walsh and Padraic Fallon, Trinity Col Dublin, Ireland; Wuzhou Wan and Philip Murphy, NIAID.

IL-2 is a cytokine essential to many kinds of immune activation, as well as suppressing autoimmune-disease-associated cytokine IL-17. Now researchers have shown that IL-2 suppresses IL-17 via STAT5, a transcription factor that binds and blocks regions of the IL-17 gene that are normally bound and activated by STAT3.
5. Macrophages fight cancer
G.L. Beatty et al.,”CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans,” Science, 331:1612-16, 2011. Evaluated by Rienk Offringa, German Cancer Res Cen (DKFZ); Albert Deisseroth, Sidney Kimmel Cancer Center.

A human trial of anti-cancer combination therapy reveals that an antibody designed to activate CD40 receptor, which reactivates suppressed anti-cancer immunity, functions by turning on macrophages rather than T cells, resulting in cancer regression in some patients.
6. Inflammation to apoptosis
G. Yeretssian et al., “Non-apoptotic role of BID in inflammation and innate immunity,” Nature, 474:96-99, 2011. Evaluated by Brigitte Huber, Tufts Univ Sch of Med.

Researchers find a new link between inflammation and apoptosis via the Bcl-2 family member BID. A known player in apoptosis, the BID signaling molecule was also shown to play an important role in conveying inflammatory signals.


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