Articles in 2011

Identification of the mechanisms that drive the transition from acute to chronic pain could lead to new treatments. Now, Zhizhong Pan and colleagues demonstrate that chronic pain causes epigenetic downregulation of GAD65 and results in inhibitory neurotransmission deficits in the brainstem of rats.

Microsatellite instability (MSI) due to alterations in DNA repair genes leads to carcinogenesis, but it also correlates with better prognosis and therapy response. Little is known of the contribution of altered noncoding sequences to MSI tumorigenesis. This report identifies a deletion in an MSI intronic region leading to the expression of a truncated chaperone, which shows dominant-negative effects on its wild-type counterpart. Acting as an endogenous inhibitor of a protumorigenic chaperone, the expression of the truncated variant associates with better prognosis in humans and may contribute to the overall limited malignancy of MSI tumors.

BRCA1 loss of function is considered to promote tumorigenesis through impairment of the protein's role in DNA damage repair. By studying BRCA1 mutations that do not affect this function but still confer cancer predisposition, this report identifies a new function of BRCA1, the repression of miR-155 through modulation of HDAC activity. miR-155 increase correlates with BRCA1 loss or mutation in humans, and it likely to mediate some of the oncogenic effects of BRCA1 deficiency.

Rapidly progressive glomerulonephritis (RPGN) is a form of severe kidney injury that can lead to promptly lethal renal failure. Pierre-Louis Tharaux and colleagues report that HB-EGF is upregulated in RPGN, resulting in activation of EGFR in podocytes and their dysfunction. They further show that genetic loss of expression of HB-EGF or EGFR in a mouse model is protective, whereas pharmacological inhibition of EGFR, even after disease onset, is therapeutic. These results suggest a possible avenue of treatment for this potentially devastating condition.

Whether there exists a human memory T cell population with stem cell–like properties of self-renewal and multipotency is under active investigation. Here Gattinoni et al. characterize a subset of human T cells that phenotypically resemble naive T cells yet have properties associated with memory T cells. These T cells show enhanced ability to self renew and to give rise to differentiated memory cell subsets, suggesting a stem cell–like functionality.

People with brain cancers called gliomas often have seizures due to secretion of the excitatory neurotransmitter glutamate from the tumor. Now, Harald Sontheimer and his colleagues report that blockade of a cystine-glutamate transporter in tumor cells by an FDA-approved drug can reduce glioma-induced epilepsy in mice.

To date, the dogma in the field has been that RANKL, an essential cytokine in osteoclast maturation, is released by osteoblasts as a way to coordinate bone growth and bone loss during adult bone remodeling. Now, Hiroshi Takayanagi and colleagues, as well as Charles O'Brien and colleagues, have independently found that osteocytes are the predominant source of RANKL in the adult mouse. As RANKL signaling is a key target in treating osteoporosis, these results have potentially important implications for disease management.

The activation of stress kinases, such as p38 MAPK, is believed to be detrimental to normal cellular processes. However, Umut Ozcan and his colleagues now show that p38 MAPK is actually beneficial, as in mice it increases the mRNA stability and nuclear localization of Xbp1s, a crucial factor in resolving endoplasmic reticulum stress and improving glucose homeostasis. These results suggest a possible indirect way of targeting XBP1s in the treatment of type 2 diabetes.

New vaccine candidates are urgently needed for the control and prevention of Mycobacterium tuberculosis (Mtb) infection. Kari Sweeney and her colleagues now report that an attenuated strain of Mycobacterium smegmatis expressing the esx-3 genes from Mtb induces effective CD4⁺ T cell dependent immunity against infection with Mtb in mice. The study offers a new avenue for the identification of protective immunogens in Mtb infection and a candidate vaccine platform warranting further study.

Imatinib has been proposed as a therapy for gastrointestinal stromal tumors, owing to its side effects on KIT, a kinase often mutated in this type of tumor. This report shows that a key aspect of imatinib's effect is its modulation of antitumor immune responses by a mechanism regulating Ido expression. Combining imatinib with CTLA-4 blockade emerges as a potential efficacious therapeutic approach for gastrointestinal stromal tumors.

By functionally isolating stem cells (LSCs) from individuals with leukemia and parsing our their gene expression, Dick and his colleagues find that LSCs have heterogeneous surface markers and frequencies and possess a gene expression profile resembling that of normal hematopoietic stem cells. The gene expression program derived from LSCs could be a general predictor of disease outcome, stratifying risk for cytogenetically normal patients, which suggests that stemness underlies leukemia aggressiveness.

People with mutations in ATGL, a gene involved in lipid catabolism, suffer from neutral lipid storage disease and often from cardiomyopathy. Rudolf Zechner and his colleagues now show in mice that Atgl activity in cardiac muscle produces key lipid ligands for PPAR-α, a transcription factor that regulates proper lipid metabolism and fuel burning in this tissue. These results may explain the mechanisms responsible for the cardiomyopathy and offer a potential target for treatment.

Many mechanisms contribute to type 2 diabetes, but few connections have established a pathway from diet to disease. Jamey Marth and his colleagues now provide a pathway to diet-induced obesity–associated diabetes that identifies defects in protein glycosylation in pancreatic beta cells as an early pathogenic step. This change results in reduced glucose transport and induces systemic disease signs, including impaired glucose tolerance and insulin resistance.

Postpartum involution of the mammary gland is a recognized risk factor for breast cancer. This report identifies a mechanism that could be at least partially responsible for the increased risk, involving both the elevated expression of COX-2 and its interaction with extracellular collagen, the deposition of which occurs during postpartum involution. Both these factors promote tumor growth and invasion in mice and correlate with poor prognosis in young women with breast cancer. The data suggest that ibuprofen treatment during involution is a safe and effective approach to diminish pregnancy-associated cancer.

The miR200 family regulates EMT through E-cadherin modulation and has been proposed to contribute to metastasis thusly. This report identifies a promoting role of miR-200 in metastatic colonization that involves a novel target, the tumor secretome. The correlation between miR-200 and metastasis in people with cancer supports the relevance of this biphasic, multifaceted role of miR-200.

Notch, a molecule widely known for its role in development and cancer, regulates hepatic glucose metabolism by offsetting excessive glucose production. Given that a series of Notch antagonists are in clinical trials against cancer, they could also be useful against type 2 diabetes.

This report identifies PICT1 as a new regulator of p53. PICT1 binds the ribosomal protein RPL11 and prevents its release from the nucleolus, precluding RPL11 from inhibiting MDM2 activity. Loss of PICT1 increases p53 abundance and protects from tumorigenesis in mice. PICT1 is also a prognostic marker in human cancers. This p53-dependent protumorigenic function is in contrast with previous reports suggesting a tumor-suppressor role for PICT1.

Focal segmental glomerulosclerosis (FSGS), or kidney scarring, is difficult to treat and is often only curable with kidney transplantation. However, FSGS often recurs after transplantation, and ~40 years ago, an unknown soluble factor in the recipient was hypothesized to exist to explain such cases. Jochen Reiser and his colleagues use data from human and mouse studies to show that soluble uPAR may be the long-sought-after soluble factor.

Germinal center B cell development is promoted by T follicular helper cells. Chen Dong and his colleagues show that Foxp3⁺ regulatory T cells expressing Bcl6 and CXCR5, two molecules highly expressed in T follicular helper cells, are present in humans and mice and arise from natural regulatory T cells. In vivo, these CXCR5⁺Bcl6⁺ regulatory T cells modulate germinal center responses.

Charcot-Marie-Tooth type 2 disease is characterized by peripheral axon loss and motor and sensory dysfunction. Constantin d'Ydewalle et al. demonstrate that these abnormalities are caused by drops in tubulin acetylation and can be normalized in mice with drugs that restore this acetylation.