Vanadium and bone development: putative signaling pathwaysThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and  Phosphoproteins—12th International Conference.

Vanadium is a trace element present in practically all cells in plants and animals. It exerts interesting actions in living systems. At pharmacological doses, vanadium compounds display relevant biological actions such as mimicking insulin and growth factors as well as having osteogenic activity. Some vanadium compounds also show antitumoral properties. The importance of vanadium in bone arises from the studies developed to establish the essentiality of this element in animals and humans. Bone tissue, where the element seems to play an important role, accumulates great amounts of vanadium. This paper reviews the physiology of osteoblasts, the involvement of different growth factors on bone development, and the effects of vanadium derivatives on the skeletal system of animal models and bone-related cells. Two cellular lines are discussed in particular; one derived from a rat osteosarcoma (UMR106) and the other is a nontransformed osteoblast cell line (MC3T3-E1). The effects of different growth factors and their mechanisms of action in these cellular lines are reviewed. These models of osteoblasts are especially useful in understanding the intracellular signaling pathways of vanadium derivatives in hard tissues. Vanadium uses an intricate interplay of intracellular mechanisms to exert different biochemical and pharmacological actions. The effects of vanadium derivatives on some cellular signaling pathways related to insulin are compiled in this review. The comprehension of these intracellular signaling pathways may facilitate the design of vanadium compounds with promising therapeutic applications as well as the understanding of secondary side effects derived from the use of vanadium as a therapeutic agent.

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TGF-Β Family Inhibitors Blunt Adipogenesis Via Non-Canonical Regulation Of SMAD Pathways

10.1101/2020.03.12.988568 ◽

2020 ◽

Author(s):

Senem Aykul ◽

Jordan Maust ◽

Monique Floer ◽

Erik Martinez-Hackert

Keyword(s):

Growth Factors ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Feedback Loop ◽

Adipose Tissues ◽

Intracellular Signaling Pathways ◽

Family Growth ◽

Pathological Conditions ◽

Adipocyte Hypertrophy ◽

Energy Surplus

ABSTRACTAdipose tissues (AT) expand in response to energy surplus through adipocyte hypertrophy and hyperplasia (i.e., adipogenesis). The latter is a process by which multipotent precursors differentiate into mature adipocytes. This process is directed by growth factors and cytokines, including members of the TGF-β family, which regulate intracellular signaling pathways that control adipogenic transcriptional programs. As ectopic adipogenesis has been linked with metabolic syndrome and other pathological conditions, we undertook to establish how TGF-β family growth factors and their inhibitors regulate this process in a 3T3-L1 adipogenesis model. We found that intracellular SMAD1/5/8 signaling pathways are activated while SMAD2/3 pathways are suppressed in differentiating cells. Addition of SMAD1/5/8 pathway activating ligands promoted cell proliferation, while SMAD2/3 pathway activating ligands suppressed adipocyte formation. We identified several ligand traps that blunted 3T3-L1 adipogenesis. Strikingly, anti-adipogenic traps and ligands exploited the same mechanism of regulation involving a negative feedback loop that links SMAD2/3 activation with SMAD1/5/8 hyper-phosphorylation, cytoplasmic retention, and reduced signaling. The identified anti-adipogenic traps could be used to control hyperplastic AT expansion and its associated pathological conditions.

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Fibroblast growth factor and cyclic AMP (cAMP) synergistically activate gene expression at a cAMP response element

Molecular and Cellular Biology ◽

10.1128/mcb.14.11.7546-7556.1994 ◽

1994 ◽

Vol 14 (11) ◽

pp. 7546-7556

Author(s):

Y Tan ◽

K G Low ◽

C Boccia ◽

J Grossman ◽

M J Comb

Keyword(s):

Gene Expression ◽

Growth Factors ◽

Growth Factor ◽

Cyclic Amp ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Gene Activation ◽

Fibroblast Growth ◽

Camp Response Element ◽

Intracellular Signaling Pathways

Growth factors and cyclic AMP (cAMP) are known to activate distinct intracellular signaling pathways. Fibroblast growth factor (FGF) activates ras-dependent kinase cascades, resulting in the activation of MAP kinases, whereas cAMP activates protein kinase A. In this study, we report that growth factors and cAMP act synergistically to stimulate proenkephalin gene expression. Positive synergy between growth factor- and cAMP-activated signaling pathways on gene expression has not been previously reported, and we suggest that these synergistic interactions represent a useful model for analyzing interactions between these pathways. Transfection and mutational studies indicate that both FGF-dependent gene activation and cAMP-dependent gene activation require cAMP response element 2 (CRE-2), a previously characterized cAMP-dependent regulatory element. Furthermore, multiple copies of this element are sufficient to confer FGF regulation upon a minimal promoter, indicating that FGF and cAMP signaling converge upon transcription factors acting at CRE-2. Among many different ATF/AP-1 factors tested, two factors, ATF-3 and c-Jun, stimulate proenkephalin transcription in an FGF- or Ras-dependent fashion. Finally, we show that ATF-3 and c-Jun form heterodimeric complexes in SK-N-MC cells and that the levels of both proteins are increased in response to FGF but not cAMP. Together, these results indicate that growth factor- and cAMP-dependent signaling pathways converge at CRE-2 to synergistically stimulate gene expression and that ATF-3 and c-Jun regulate proenkephalin transcription in response to both growth factor- and cAMP-dependent intracellular signaling pathways.

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