CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response.

Gene regulation by cytokine-activated transcription factors of the signal transducer and activator of transcription (STAT) family requires serine phosphorylation within the transactivation domain (TAD). STAT1 and STAT3 TAD phosphorylation occurs upon promoter binding by an unknown kinase. Here, we show that the cyclin-dependent kinase 8 (CDK8) module of the Mediator complex phosphorylated regulatory sites within the TADs of STAT1, STAT3, and STAT5, including S727 within the STAT1 TAD in the interferon (IFN) signaling pathway. We also observed a CDK8 requirement for IFN-γ-inducible antiviral responses. Microarray analyses revealed that CDK8-mediated STAT1 phosphorylation positively or negatively regulated over 40% of IFN-γ-responsive genes, and RNA polymerase II occupancy correlated with gene expression changes. This divergent regulation occurred despite similar CDK8 occupancy at both S727 phosphorylation-dependent and -independent genes. These data identify CDK8 as a key regulator of STAT1 and antiviral responses and suggest a general role for CDK8 in STAT-mediated transcription. As such, CDK8 represents a promising target for therapeutic manipulation of cytokine responses.

Sleep profile and symptoms of sleep disorders in patients with stable mild to moderate chronic obstructive pulmonary disease.

BACKGROUND: Sleep problems associated with chronic obstructive pulmonary disease may have an important impact on quality of life and health outcome measures in patients. The aim of this study was to prospectively assess differences in symptom profile and polysomnographic parameters in patients with stable mild to moderate COPD and age, gender, and body-mass-index matched controls without airflow obstruction. METHODS: The Sleep Disorders Questionnaire was administered to both patients and controls prior to clinical and polysomnographic evaluation. Responses obtained from the questionnaire were used to construct four independent symptom scales: sleep apnea, periodic limb movement syndrome, psychiatric sleep disorder, and narcolepsy. Associations between each diagnostic scale and sleep parameters were considered by means of multiple analyses of covariance. RESULTS: Fifty-two patients with mild-to-moderate COPD (age 62±8 years, BMI 29±7 kg/sqm) and 52 age, gender, and body-weight matched controls without COPD were studied. Patients with COPD had overall lower sleep efficiency, a lower total sleep time, and lower mean overnight oxygen saturation compared to controls. Patients with COPD were significantly more likely to report symptoms such as insomnia and difficulty in initiating and maintaining sleep, resulting in overall higher psychiatric sleep disorder scale scores in patients compared with controls. Minimum oxygen saturation was an independent predictor for all symptom scales. After correcting for potentially confounding factors, including pack/years of smoking, total sleep time, sleep efficiency, arousal index, mean and minimum oxygen saturation, and apnea-hypopnea-index, the between group-differences for both the periodic limb movement and psychiatric sleep disorder scale scores remained statistically significant. CONCLUSIONS: We observed significant differences in both quantity and quality of sleep between patients with stable mild to moderate chronic obstructive pulmonary disease and respective controls.