mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia.

Pulmonary arterial vascular smooth muscle (PAVSM) cell proliferation is a key pathophysiological component of vascular remodeling in pulmonary arterial hypertension (PAH) for which cellular and molecular mechanisms are poorly understood. The goal of our study was to determine the role of mammalian target of rapamycin (mTOR) in PAVSM cell proliferation, a major pathological manifestation of vascular remodeling in PAH. Our data demonstrate that chronic hypoxia promoted mTOR(Ser-2481) phosphorylation, an indicator of mTOR intrinsic catalytic activity, mTORC1-specific S6 and mTORC2-specific Akt (Ser-473) phosphorylation, and proliferation of human and rat PAVSM cells that was inhibited by siRNA mTOR.

Interferons modulate mitogen-induced protein synthesis in airway smooth muscle.

Severe asthma is characterized by increased airway smooth muscle (ASM) mass due, in part, to ASM cell growth and contractile protein expression associated with increased protein synthesis. Little is known regarding the combined effects of mitogens and interferons on ASM cytosolic protein synthesis. We demonstrate that human ASM mitogens including PDGF, EGF, and thrombin stimulate protein synthesis.

Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation.

Lymphangioleiomyomatosis (LAM), a rare pulmonary disorder, manifests as an abnormal neoplastic growth of smooth muscle-like cells within the lungs. Mutational inactivation of tumor suppressor tuberous sclerosis complex 2 (TSC2) in LAM constitutively activates the mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) signaling pathway and promotes neoplastic growth of LAM cells. In many cell types, type I interferon beta (IFNbeta) inhibits proliferation and induces apoptosis through signal transducers and activators of transcription (STAT)-dependent and STAT-independent signaling pathways, one of which is the mTOR/S6K1 signaling pathway.

Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis.

The loss of TSC2 function is associated with the pathobiology of lymphangioleiomyomatosis (LAM), which is characterized by the abnormal proliferation, migration, and differentiation of smooth muscle-like cells within the lungs. Although the etiology of LAM remains unknown, clinical and genetic evidence provides support for the neoplastic nature of LAM. The goal of this study was to determine the role of tumor suppressor TSC2 in the neoplastic potential of LAM cells.

Src is necessary and sufficient for human airway smooth muscle cell proliferation and migration.

Airway smooth muscle (ASM) hypertrophy and hyperplasia, important pathological features in chronic severe asthma, likely contribute to irreversible airflow obstruction. Despite considerable research effort, the precise cellular mechanisms that modulate ASM growth remain unknown. Src, a nonreceptor tyrosine kinase proto-oncogene, reportedly modulates cell proliferative responses to growth factors, contractile agonists, and inflammatory mediators.