Understanding signaling cascades in melanoma

Understanding regulatory pathways involved in melanoma development and progression has advanced significantly in recent years. It is now appreciated that melanoma is the result of complex changes in multiple signaling pathways that affect growth control, metabolism, motility and the ability to escape cell death programs. Here we review the major signaling pathways currently known to be deregulated in melanoma with an implication to its development and progression. Among these pathways are Ras, B-Raf, MEK, PTEN, phosphatidylinositol-3 kinase (PI3Ks) and Akt which are constitutively activated in a significant number of melanoma tumors, in most cases due to genomic change. Other pathways discussed in this review include the [Janus kinase/signal transducer and activator of transcription (JAK/STAT), transforming growth factor-beta pathways which are also activated in melanoma, although the underlying mechanism is not yet clear. As a paradigm for remodeled signaling pathways, melanoma also offers a unique opportunity for targeted drug development.Fil: Lopez Bergami, Pablo Roberto. Sanford-burnham Medical Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fitchmann, B. Sanford-burnham Medical Research Institute; Estados UnidosFil: Ronai, Ze´ev. Sanford-burnham Medical Research Institute; Estados Unido

Retroactivity attenuation in signaling cascades

It has been shown in an earlier work that impedance-like effects, called retroactivity, are found at the interconnection of biomolecular systems just as they occur in several engineering systems. These effects are particularly relevant in signaling cascades that have several downstream targets. These cascades have been extensively studied to determine how a stimulus at the top of the cascade is transmitted and amplified as it propagates toward the bottom of the cascade. In principle, because of retroactivity, a perturbation at the bottom of the cascade can propagate upstream. In this paper, we study the extent to which this propagation occurs by analytically finding retroactivity gains at each stage of the cascade. These gains determine whether a perturbation at the bottom of the cascade is amplified or attenuated as it propagates upstream.United States. Air Force Office of Scientific Research (Grant FA9550-09-1-0211

Expanding the mitogen-activated protein kinase (MAPK) universe : an update on MAP4Ks

Phosphorylation-mediated signaling cascades control plant growth and development or the response to stress conditions. One of the best studied signaling cascades is the one regulated by MITOGEN-ACTIVATED PROTEIN KINASEs (MAPKs). However, MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE KINASEs (MAP4Ks) are hardly explored. Here, we will give a comprehensive overview of what is known about plant MAP4Ks and highlight some outstanding questions associated with this largely uncharacterized class of kinases in plants

Optimal length and signal amplification in weakly activated signal transduction cascades

Weakly activated signaling cascades can be modeled as linear systems. The input-to-output transfer function and the internal gain of a linear system, provide natural measures for the propagation of the input signal down the cascade and for the characterization of the final outcome. The most efficient design of a cascade for generating sharp signals, is obtained by choosing all the off rates equal, and a ``universal'' finite optimal length.Comment: 27 pages, 10 figures, LaTeX fil

Molecular determinants of acute kidney injury

BACKGROUND: Acute kidney injury (AKI) is a condition that leads to a rapid deterioration of renal function associated with impairment to maintain electrolyte and acid balance, and, if left untreated, ultimately irreversible kidney damage and renal necrosis. There are a number of causes that can trigger AKI, ranging from underlying conditions as well as trauma and surgery. Specifically, the global rise in surgical procedures led to a substantial increase of AKI incidence rates, which in turn impacts on mortality rates, quality of life and economic costs to the healthcare system. However, no effective therapy for AKI exists. Current approaches, such as pharmacological intervention, help in alleviating symptoms in slowing down the progression, but do not prevent or reverse AKI-induced organ damage. METHODS: An in-depth understanding of the molecular machinery involved in and modulated by AKI induction and progression is necessary to specifically pharmacologically target key molecules. A major hurdle to devise a successful strategy is the multifactorial and complex nature of the disorder itself, whereby the activation of a number of seemingly independent molecular pathways in the kidney leads to apoptotic and necrotic events. RESULTS: The renin-angiotensin-aldosterone-system (RAAS) axis appears to be a common element, leading to downstream events such as triggers of immune responses via the NFB pathway. Other pathways intricately linked with AKI-induction and progression are the tumor necrosis factor alpha (TNF) and transforming growth factor beta (TGF) signaling cascades, as well as a number of other modulators. Surprisingly, it has been shown that the involvement of the glutamatergic axis, believed to be mainly a component of the neurological system, is also a major contributor. CONCLUSIONS: Here we address the current understanding of the molecular pathways evoked in AKI, their interplay, and the potential to pharmacologically intervene in the effective prevention and/or progression of AKI

A novel algorithm for detecting differentially regulated paths based on gene set enrichment analysis

Motivation: Deregulated signaling cascades are known to play a crucial role in many pathogenic processes, among them are tumor initiation and progression. In the recent past, modern experimental techniques that allow for measuring the amount of mRNA transcripts of almost all known human genes in a tissue or even in a single cell have opened new avenues for studying the activity of the signaling cascades and for understanding the information flow in the networks