Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging.

The mammalian target of rapamycin (mTOR) signaling pathway has been studied in the context of an impressive number of biological processes and disease states, including major diseases of the lung such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, as well as the rare condition lymphangioleiomyomatosis. The involvement of mTOR in so many disease states (in and out of the lung) raises the question how one signaling pathway can have overlapping but diverse roles seemingly everywhere. Findings in the last decade have placed the mTOR pathway in a new context as an important, conserved mediator of the aging process.

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging.

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus.

RB and lamins in cell cycle regulation and aging.

While speculation has centered on a role for nuclear lamins in tumor progression for many years, most of the diseases that have been linked to lamin mutation are dystrophic in nature, often limiting the proliferation potential of affected cells in vivo and in vitro. Nevertheless, these lamin mutations, particularly in the LMNA gene that encodes A-type lamins, have provided an interesting tool set to understand functions of nuclear intermediate filament proteins in cell cycle progress and various means of exit, including quiescence, senescence, and differentiation down various lineages. The picture that has emerged is complex with lamins controlling the activity of key cell cycle factors such as the retinoblastoma protein (RB) and interacting with several important signal transduction pathways.

Drugs that modulate aging: the promising yet difficult path ahead.

Once a backwater in medical sciences, aging research has emerged and now threatens to take the forefront. This dramatic change of stature is driven from 3 major events. First and foremost, the world is rapidly getting old.

Realizing the allosteric potential of the tetrameric protein kinase A RIα holoenzyme.

PKA holoenzymes containing two catalytic (C) subunits and a regulatory (R) subunit dimer are activated cooperatively by cAMP. While cooperativity involves the two tandem cAMP binding domains in each R-subunit, additional cooperativity is associated with the tetramer. Of critical importance is the flexible linker in R that contains an inhibitor site (IS).

Redox regulation of cAMP-dependent protein kinase signaling: kinase versus phosphatase inactivation.

Many components of cellular signaling pathways are sensitive to regulation by oxidation and reduction. Previously, we described the inactivation of cAMP-dependent protein kinase (PKA) by direct oxidation of a reactive cysteine in the activation loop of the kinase. In the present study, we demonstrate that in HeLa cells PKA activity follows a biphasic response to thiol oxidation.

A simple electrostatic switch important in the activation of type I protein kinase A by cyclic AMP.

Cyclic AMP activates protein kinase A by binding to an inhibitory regulatory (R) subunit and releasing inhibition of the catalytic (C) subunit. Even though crystal structures of regulatory and catalytic subunits have been solved, the precise molecular mechanism by which cyclic AMP activates the kinase remains unknown. The dynamic properties of the cAMP binding domain in the absence of cAMP or C-subunit are also unknown.

Isoform specific differences in binding of a dual-specificity A-kinase anchoring protein to type I and type II regulatory subunits of PKA.

Dual-specificity AKAPs bind to type I (RI) and type II (RII) regulatory subunits of cAMP-dependent protein kinase A (PKA), potentially recruiting distinct cAMP responsive holoenzymes to a given intracellular location. To understand the molecular basis for this "dual" functionality, we have examined the pH-dependence, the salt-dependence, and the kinetics of binding of the A-kinase binding (AKB) domain of D-AKAP2 to the regulatory subunit isoforms of PKA. Using fluorescence anisotropy, we have found that a 27-residue peptide corresponding to the AKB domain of D-AKAP2 bound 25-fold more tightly to RIIalpha than to RIalpha.