Serum Withdrawal-Induced Apoptosis in Thyroid Cells Is Caused by Loss of Fibronectin-Integrin Interaction*

Matola, Tiziana Di; Müeller, Frank; Fenzi, Gianfranco; Rossi, Guido; Bifulco, Maurizio; La, Marzano; Vitale, Mario

doi:10.1210/jcem.85.3.6425

Cited by 13 publications

(4 citation statements)

References 29 publications

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“…Fibronectin is implicated in cell survival through activation of the focal adhesion kinase signaling pathway, and could regulate expression of anti‐apoptotic genes such as bcl‐2 (46). Disruption of fibronectin/integrin signaling has been reported to be the cause of serum‐deprived thyroid cell anoikis (47), and serum starvation‐induced apoptosis of SMCs was associated with cellular fibronectin degradation (48). Soluble fibronectin peptides induce fibroblast apoptosis (49) and fibroblast survival requires interaction of integrins with the cell‐(via RGD) and the heparin binding domain of fibronectin (50).…”

Section: Discussionmentioning

confidence: 99%

Pericellular plasmin induces smooth muscle cell anoikis

et al. 2003

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Smooth muscle cell (SMC) rarefaction is involved in the development of several vascular pathologies. We suggest that the plasminogen activation system is a potential extracellular signal that can induce pericellular proteolysis and apoptosis of vascular SMCs. Using primary cultures of arterial SMCs, we show that plasmin generated from plasminogen on the cell surface induces cell retraction and fibronectin fragmentation, leading to detachment and morphological/biochemical changes characteristic of apoptosis (also called anoikis). The generation of cell-bound plasmin mediated by tissue-type plasminogen activator (t-PA), constitutively expressed by VSMCs, requires binding of plasminogen to the cell surface and is inhibited by epsilon-aminocaproic acid (IC50=0.9+/-0.2 mM), a competitor of plasminogen binding to membrane glycoproteins. Conversely, addition of alpha2-antiplasmin, which blocks free plasmin in the cell supernatant, could not fully prevent anoikis. Finally, an MMP inhibitor failed to prevent VSMC anoikis, arguing for a direct involvement of plasmin in this phenomenon. Indeed, similar changes are induced by plasmin directly added to VSMCs or to arterial rings, ex-vivo. We show for the first time that pathological anoikis can be triggered by a process that requires functional assembly of the plasminogen activation system on the surface of VSMCs.

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Section: Discussionmentioning

confidence: 99%

Pericellular plasmin induces smooth muscle cell anoikis

et al. 2003

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“…Therefore we first determined whether the TSH/ERK and the TSH/CREB pathways are intact in TAD‐2 cells. As demonstrated before, integrin activation is sufficient to maximal ERK phosphorylation and thus this cell line is not suitable to study the TSH/ERK pathway in physiologic adherent conditions (Di Matola et al, ; Illario et al, ). Forskolin, a cAMP‐independent PKA activator, induced a maximal CREB phosphorylation lasting 30 min (Fig.…”

Section: Discussionmentioning

confidence: 97%

Ras Oncoprotein Disrupts the TSH/CREB Signaling Upstream Adenylyl Cyclase in Human Thyroid Cell

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Salzano

et al. 2014

Journal Cellular Physiology

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Activating mutations in RAS genes and p21 Ras overactivation are common occurrences in a variety of human tumors. p21 Ras oncoproteins deregulate a number of signaling pathways, dedifferentiating the thyroid cell, and negatively regulating the expression of thyroid specific genes. In rat thyroid cells, Ras oncoproteins inhibit the TSH pathway by reducing PKA activity and thus the expression of thyroid specific genes, while in mouse melanocytes, Ras oncoproteins reduce the αMSH-stimulated cAMP signaling by increasing the expression of the phosphodiesterase-4B. Given these cell-dependent differences, we investigated if and how the TSH/CREB pathway is modulated by Ras oncoprotein in a human thyroid cell line. CREB phosphorylation was stimulated by TSH and forskolin in TAD-2 cells. Ras(V12) expression negatively regulated the TSH-stimulated CREB phosphorylation but was ineffective on forskolin-stimulated CREB phosphorylation. Phosphodiesterase inhibition by IBMX enhanced TSH-stimulated CREB phosphorylation, but did not restore TSH-stimulated CREB phosphorylation inhibited by Ras oncoprotein. These data indicate that Ras oncoprotein disrupts the TSH/CREB pathway, upstream adenylyl cyclase, and highlight the existence of mechanisms of interaction between Ras and the cAMP pathway different in human and in rat thyroid cells.

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“…The relevance of our ®ndings made in an established rat cell line to thyroid cells in vivo remains to be established. Although primary (Di Matola et al, 2000) and established (Vitale et al, 1999) human thyroid cells reportedly undergo more extensive anoikis than established rat thyroid cell lines, the e ects of Ras on anoikis have not been reported. However, primary human thyrocytes, like WRT cells, are resistant to a variety of apoptotic insults including activation of death receptors (Arscott et al, 1997;Bretz et al, 1999).…”

Section: Discussionmentioning

confidence: 98%