“We learned that this new protein, like NF-AT, binds to calcineurin, and is a substrate for calcineurin’s protein phosphatase activity.”

We showed that increasing the abundance of an endogenous protein that is normally present within cells of the heart could prevent cardiac hypertrophy provoked by a variety of stimuli, without deleterious effects on the unstressed heart. This was a novel principle, potentially leading to new therapeutic approaches to prevent heart failure.

We had demonstrated previously that MCIP1 (also known as DSCR1) functions in mammalian cells as an endogenous inhibitor of the protein phosphatase calcineurin, which is a critical signaling molecule for many important biological processes, including cardiac hypertrophy. Several labs now have exploited the inhibitory actions of MCIP1 on calcineurin to define the role of this signaling pathway in a number of different stress responses and disease states, and to suggest new therapeutic approaches.

Our hearts have defense mechanisms that protect us from stresses that can cause the heart to enlarge and fail, but these defenses can be overwhelmed by disease. If in the future we can find ways to stimulate a higher level of function of these natural defenses in the heart by the use of new drugs or biological agents, we may create novel measures to prevent heart failure and death from cardiovascular disease.

In 1998, my lab at the University of Texas Southwestern Medical Center in Dallas had been the first to propose that calcineurin functions as a key regulator of contraction-dependent gene regulation (e.g., adaptive responses to exercise training) and fiber type specialization in skeletal muscle, and Eric Olson and his colleagues had identified calcineurin also to be an important regulator of hypertrophic growth of the heart. For the next several years, we maintained a fruitful and fast-paced collaboration with Eric and his lab in studies of calcineurin signaling in skeletal and cardiac muscle. A post-doctoral fellow in my lab, Beverly Rothermel, identified a gene in mammalian databases that includes a structural motif similar to the important calcineurin substrate NF-AT, which transduces calcineurin signals to the nucleus, and we embarked on studies to characterize the expression and function of this new gene, which had been annotated as DSCR-1 because the human gene was located on Chromosome 21 within the Down Syndrome Critical Region. We learned that this new protein, like NF-AT, binds to calcineurin, and is a substrate for calcineurin’s protein phosphatase activity. Unlike NF-AT, however, the protein encoded by the DSCR1 gene does not transduce signals, but functions as an inhibitor of calcineurin activity. In addition, its expression in heart and skeletal muscle is potently up-regulated by calcineurin signaling, thereby creating a negative feedback circuit, presumably to protect cells from deleterious consequences of unrestrained calcineurin activity. Based on these functional properties, we renamed the protein MCIP-1 (Muscle-selective Calcineurin Interacting Protein-1), and went on to study the consequences of experimentally varying the abundance of MCIP-1 in intact tissues of transgenic and gene knock-out mice. Beverly Rothermel has gone on to establish her independent lab, also located at the University of Texas Southwestern Medical Center at Dallas and has performed notable research on MCIP-1 subsequently.