Protein form and function

A team of researchers from Harvard Medical School and Whitehead Institute report that, at least in the case of one variety of cavefish, one agent of evolutionary change is the heat shock protein known as HSP90.

The most common fungal pathogen in humans, Candida albicans, rarely develops resistance to the antifungal drug amphotericin B (AmB).  This has been puzzling as the drug has been in clinical use for over 50 years. Whitehead Institute scientists have now discovered why.  The genetic mutations that enable certain strains of C. albicans to resist AmB simultaneously render it highly susceptible to environmental stressors and disarm its virulence factors.

Using a discovery platform whose components range from yeast cells to human stem cells, Whitehead Institute scientists have identified a novel Parkinson’s disease drug target and a compound capable of repairing neurons derived from Parkinson’s patients.

By directly altering the gene coding for the prion protein (PrP), Whitehead Institute researchers have created mouse models of two neurodegenerative prion diseases, each of which manifests in different regions of the brain.  These new models for fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD) accurately reflect the distinct patterns of destruction caused by the these diseases in humans.  Remarkably, as different as each disease is, they both spontaneously generate infectious prions.

For more than 125 years, scientists have been peering through microscopes, carefully watching cells divide. Until now, however, none has actually seen how cells manage to divide precisely into two equally-sized daughter cells during mitosis. Such perfect division depends on the position of the mitotic spindle (chromosomes, microtubules, and spindle poles) within the cell, and it’s now clear that human cells employ two specific mechanisms during the portion of division known as anaphase to correct mitotic spindle positioning.

Protein production or translation is tightly coupled to a highly conserved stress response—the heat shock response and its primary regulator, heat shock factor 1 (HSF1)—that cancer cells rely on for survival and proliferation, according to Whitehead Institute researchers. In mouse models of cancer, therapeutic inhibition of translation interrupts HSF1’s activity, dramatically slowing tumor growth and potentially rendering drug-resistant tumors responsive to other therapies.

Researchers at Whitehead Institute have identified a key target protein of glucocorticoids, the drugs that are used to increase red blood cell production in patients with certain types of anemia, including those resulting from trauma, sepsis, malaria, kidney dialysis, and chemotherapy.

Whitehead Institute researchers have identified a protein complex that, when mutated, sends the master growth regulatory pathway known as mTORC1 into overdrive. Researchers believe that mutations in this complex could serve as biomarkers to predict response to rapamycin treatment in cancer patients.

In a surprising finding that helps explain fundamental behaviors of normal and diseased cells, Whitehead Institute scientists have discovered a set of powerful gene regulators dubbed “super-enhancers” that control cell state and identity.

A team of scientists from Whitehead Institute and the University of Texas Southwestern Medical Center has added markedly to the job description of prions as agents of change, identifying a prion capable of triggering a transition in yeast from its conventional single-celled form to a cooperative, multicellular structure. This change, which appears to improve yeast’s chances for survival in the face of hostile environmental conditions, is an epigenetic phenomenon—a heritable alteration brought about without any change to the organism’s underlying genome.