The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation

Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle soon after birth in mammals Although the extent to which adult cardiac myocytes are capable of cell cycle reentry is controversial and species-specific differences may exist, it appears that for the vast majority of adult cardiac myocytes the predominant form of growth postnatally is an increase in cell size (hypertrophy) not number Unfortunately, this limits the ability of the heart to restore function after any significant injury Interest in novel regenerative therapies has led to the accumulation of much information on the mechanisms that regulate the rapid proliferation of cardiac myocytes in utero, their cell cycle exit in the perinatal period, and the permanent arrest (terminal differentiation) in adult myocytes The recent identification of cardiac progenitor cells capable of giving rise to cardiac myocyte-like cells has challenged the dogma that the heart is a terminally differentiated organ and opened new prospects for cardiac regeneration In this review, we summarize the current understanding of cardiomyocyte cell cycle control in normal development and disease In addition, we also discuss the potential usefulness of cardiomyocyte self-renewal as well as feasibility of therapeutic manipulation of the cardiac myocyte cell cycle for cardiac regeneration

https://www.physiology.org/doi/pdf/10.1152/physrev.00032.2006

Cardiac Myocyte Cell Cycle Control in Development, Disease, and Regeneration

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

The idea of the importance of mounting an inflammatory response for effective immunity is supported by a multiplicity of experimental data. It is also well understood that resolution of inflammation is essential for maintaining the balance between health and disease. When the normal regulatory mechanisms are disturbed, the potential for developing chronic inflammatory diseases is increased. Inflammation is a key element in the response of the innate immune system to a variety of challenges, including those provided by bacterial and viral infection as well as by damaged or dying host cells. Here we review elements of innate immunity that lead to inflammation and some of the host mechanisms that allow for the resolution of the inflammatory responses.

Limiting inflammatory responses during activation of innate immunity

Mitogen-activated protein kinases (MAPKs) regulate critical signaling pathways involved in cell proliferation, differentiation and apoptosis. Recent studies have shown that a novel class of scaffold proteins mediates the structural and functional organization of the three-tier MAPK module. By linking the MAP3K, MAP2K and MAPK into a multienzyme complex, these MAPK-specific scaffold proteins provide an insulated physical conduit through which signals from the respective MAPK can be transmitted to the appropriate spatiotemporal cellular loci. Scaffold proteins play a determinant role in modulating the signaling strength of their cognate MAPK module by regulating the signal amplitude and duration. The scaffold proteins themselves are finely regulated resulting in dynamic intra- and inter-molecular interactions that can modulate the signaling outputs of MAPK modules. This review focuses on defining the diverse mechanisms by which these scaffold proteins interact with their respective MAPK modules and the role of such interactions in the spatiotemporal organization as well as context-specific signaling of the different MAPK modules.

/pdf/scaffold-proteins-of-map-kinase-modules-1czrn4hhlw.pdf

Scaffold proteins of MAP-kinase modules

The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

JiahuaiHAN

Papers

Activation and signaling of the p38 MAP kinase pathway