The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation.

The circadian timing system synchronizes cellular function by coordinating rhythmic transcription via a transcription-translational feedback loop. How the circadian system regulates gene expression at the translational level remains a mystery. Here, we show that the key circadian transcription factor BMAL1 associates with the translational machinery in the cytosol and promotes protein synthesis. The mTOR-effector kinase, ribosomal S6 protein kinase 1 (S6K1), an important regulator of translation, rhythmically phosphorylates BMAL1 at an evolutionarily conserved site. S6K1-mediated phosphorylation is critical for BMAL1 to both associate with the translational machinery and stimulate protein synthesis. Protein synthesis rates demonstrate circadian oscillations dependent on BMAL1. Thus, in addition to its critical role in circadian transcription, BMAL1 is a translation factor that links circadian timing and the mTOR signaling pathway. More broadly, these results expand the role of the circadian clock to the regulation of protein synthesis.

Do Interventions Intended to Increase Female Medical Student Interest in Radiology Work? Preliminary Findings.

PURPOSE: The purpose of this study is to share the preliminary findings after initiation of interventions at the medical school level, which have been suggested by the literature to increase female medical student interest in radiology at one institution. Additionally, the paper provides discussion of how to better future interventions for increasing female medical student interest. METHODS: Interventions to increase medical student exposure to radiology were implemented at the University of Massachusetts Medical School in 2012. Radiology was incorporated into the preclinical curriculum; flexible clinical experiences stressing patient contact were created for early exposure to radiology during third-year clerkships; and a 'Women in Radiology' panel was held to promote visibility of female radiologists. In addition, female radiology faculty became more involved in medical school activities and events. RESULTS: Our results suggest that early exposure in the preclinical curriculum and patient-centered electives increase overall student interest in radiology but only minimally increase female interest. Simply offering the patient-centered electives is not enough as it resulted in more male student enrollment than female (60% vs. 40%, respectively). Just one event promoting visibility of female radiologists changed female medical student perception of patient contact within radiology by a statistically significant amount. Examination of current UMass faculty radiologists by gender demonstrates that full-time, junior female radiologists-the demographic suggested to have the biggest impact on female medical students-only accounted for 4% of faculty. CONCLUSION: This article may be informative for radiology departments looking to increase female medical student interest. Required visibility of female radiologists and active publicity of female radiologists from the first preclinical year are likely to have the biggest impact in increasing female medical student interest.

Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy.

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes, whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here, we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization. This results in elevated levels of BMAL1 and a dysfunctional clock that displays abnormal timekeeping under constant conditions and exaggerated responses to phase resetting. Genetically lowering the dose of BMAL1 rescues circadian behavioral phenotypes in TSC mouse models. These findings indicate that BMAL1 deregulation is a feature of the mTOR-activated state and suggest a molecular mechanism for mitigating circadian phenotypes in a neurodevelopmental disorder.

Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1.

The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway.