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Mitogenic Signaling (mitogenic + signaling)

Distribution by Scientific Domains

Life Sciences	75%

Selected Abstracts

Altered subcellular location of phosphorylated Smads in Alzheimer's disease

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2006
Uwe Ueberham
Abstract A number of growth factors and cytokines, such as transforming growth factor beta 1 (TGF-,1), is elevated in Alzheimer's disease (AD), giving rise to activated intracellular mitogenic signaling cascades. Activated mitogenic signaling involving the mitogen-activated protein kinases (MAPKs) and other protein kinases might alter the phosphorylation states of structural proteins such as tau, resulting in hyperphosphorylated deposits. Many intracellular signaling proteins are potential targets of misregulated phosphorylation and dephosphorylation. Recently, a crosstalk between MAPKs and Smad proteins, both involved in mediating TGF-,1 signaling, has been reported. Although TGF-,1 has previously been shown to be involved in the pathogenesis of AD, the role of Smad proteins has not been investigated. In this study we thus analysed the subcellular distribution of phosphorylated Smad2 and Smad3 in the hippocampus of both normal and AD brains. Here we report on strong nuclear detection of phosphorylated Smad2 and Smad3 in neurons of control brains. In AD brains these phosphorylated proteins were additionally found in cytoplasmic granules in hippocampal neurons, within amyloid plaques and attached to neurofibrillary tangles. Our data suggest a critical role of Smad proteins in the pathogenesis of AD. [source]

A novel mechanism for mitogenic signaling via pro,transforming growth factor , within hepatocyte nuclei

HEPATOLOGY, Issue 6 2002
Bettina Grasl-Kraupp
Transforming growth factor (TGF) ,, an important mediator of growth stimulation, is known to act via epidermal growth factor receptor (EGF-R) binding in the cell membrane. Here we show by immunohistology, 2-dimensional immunoblotting, and mass spectrometry of nuclear fractions that the pro-protein of wild-type TGF-, occurs in hepatocyte nuclei of human, rat, and mouse liver. Several findings show a close association between nuclear pro-TGF-, and DNA synthesis. (1) The number of pro-TGF-,+ nuclei was low in resting liver and increased dramatically after partial hepatectomy and after application of hepatotoxic chemicals or the primary mitogen cyproterone acetate (CPA); in any case, S phase occurred almost exclusively in pro-TGF-,+ nuclei. The same was found in human cirrhotic liver. (2) In primary culture, 7% of hepatocytes synthesized pro-TGF-,, which then translocated to the nucleus; 70% of these nuclei subsequently entered DNA replication, whereas only 2% of pro-TGF-,, hepatocytes were in S phase. (3) The frequency of hepatocytes coexpressing pro-TGF-, and DNA synthesis was increased by the hepatomitogens CPA or prostaglandin E2 and was decreased by the growth inhibitor TGF-,1. (4) Treatment with mature TGF-, increased DNA synthesis exclusively in pro-TGF-,, hepatocytes, which was abrogated by the EGF-R tyrosine kinase inhibitor tyrphostin A25. In conclusion, TGF-, gene products may exert mitogenic effects in hepatocytes via 2 different signaling mechanisms: (1) the "classic" pathway of mature TGF-, via EGF-R in the membrane and (2) a novel pathway involving the presence of pro-TGF-, in the nucleus. [source]

Fibronectin, integrins, and growth control

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2001
Erik H.J. Danen
Cell proliferation is controlled not only by soluble mitogens but also by components of the extracellular matrix (ECM) such as fibronectin, to which cells adhere via the integrin family of transmembrane receptors. Input from both growth factor receptors and integrins is required to stimulate progression through the G1 phase of the cell cycle, via induction of G1 cyclins and suppression of inhibitors of the G1 cyclin-dependent kinases. Extensive crosstalk takes place between integrin and growth factor receptor signaling pathways, and mitogenic signaling is weak and transient in the absence of integrin-mediated cell adhesion. In normal untransformed cells, all of the important mitogenic signal transduction cascades, namely those downstream of the Ras and Rho family small GTPases and the phosphoinositide 3-OH kinase-PKB/Akt pathway, are regulated by integrin-mediated cell adhesion. As a result, these cells are anchorage-dependent for growth. In contrast, constitutive activity of each of these pathways has been reported in cancer cells, which not only reduces their mitogen dependence but also allows these cells to grow in an anchorage-independent fashion. © 2001 Wiley-Liss, Inc. [source]

UV Exposure, Genetic Targets in Melanocytic Tumors and Transgenic Mouse Models,

PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2005
Frank R. de Gruijl
ABSTRACT The genetic changes and corruption of kinase activity in melanomas appear to revolve around a central axis: mitogenic signaling along the RAS pathway down to transcription regulation by pRB. Epidemiological studies point to the importance of ultraviolet (UV) radiation in the etiology of melanoma, but where and how UV radiation is targeted to contribute to the oncogenic signaling remains obscure. Animal models of melanoma genesis could serve to clarify this issue, but many of these models are not responsive to UV exposure. Most interesting advances have been made by using transgenic mice that carry genetic defects that are known to be relevant to human melanoma: specifically, dysfunction in the tumor suppressive action of p161NK4a or a receptor tyrosine kinase/RAS pathway, that is constitutively activated in melanocytes. The latter types of mice appear to be most responsive to (neonatal) UV exposure. Whether this is due to a general increase in target cells by melanocytosis and a paucity or complete lack of pigment, or a possible UV-induced response of the promoter,enhancer of the transgene or a genuinely independent and additional genetic alteration caused by UV exposure needs to be established. Importantly, the full effect of UV radiation needs to be ascertained in mice with different pigmentation by varying the wavelengths, UV-B versus UV-A1, and the exposure schedules, i.e. neonatal versus adult and chronic versus intermittent overexposure. Intermittent UV-B overexposure deserves special attention because it most strongly evokes proliferative responses in melanocytes. [source]