Induction of ferritin expression by oxalomalate

Ferritin is a ubiquitous protein required for intracellular iron storage; its biosynthesis is mainly regulated by iron-regulatory proteins (IRP1 and IRP2) at post-transcriptional level. This regulation prevents iron excess from promoting the formation of reactive oxygen species (ROS). IRP1 is regulated by such factors as intracellular iron levels, the oxidants H2O2 and NO. We recently demonstrated that oxalomalate (OMA, α-hydroxy-β-oxalosuccinic acid), a competitive inhibitor of aconitase, which is an enzyme of the citric acid cycle, remarkably decreases the binding activity of IRP1. The aim of the present study was to investigate whether this molecule could affect the expression of ferritin. The RNA-binding activity of IRP1, evaluated by gel retardation assay, decreased after treatment of several cell lines with 5 mM OMA, with a maximal decrease of about 3-fold after 6 h. This effect remained almost constant up to 48 h after which it returned to basal levels. Intracellular ferritin levels, determined by Western blot analysis, increased in correlation with the OMA-induced decrease of IRP1 binding activity. Furthermore, treatment of cells with OMA caused a rise in ferritin mRNA levels. Interestingly, in cells exposed to iron challenge, OMA-induced overexpression of ferritin prevented formation of ROS and cellular lipid peroxidation. These data show that an inhibitor of aconitase, OMA, besides being involved in energetic metabolism, is able to control ferritin expression, probably through molecular mechanisms of either post-transcriptional regulation or transcriptional modulation, with advantageous consequences for the cell

Overexpression of H ferritin and upregulation of iron regulatory protein genes during differentiation of 3T3-L1 pre-adipocytes

I.F. 7.66

Novel targets for apoptosis modulation: BAG3 protein and other co-chaperones

Deregulation of apoptosis is responsible for diseases that involve defects in the death pathway, such as neoplasias, or in its inhibition, like degenerative processes. Among apoptosis- regulating molecules, a role is emerging for BAG3, a member of the BAG proteins family (BAG1L, BAG1, BAG2, BAG3, BAG4. BAG5 and BAG6) involved in cochaperoning of heat shock proteins. Through its BAG, WW and prolix-rich domains, BAG3 protein can interact with a variety of molecular partners, including Hsc70/Hsp70, phospholipase C-γ and others. It has been recently shown that, in human primary lymphoid and myeloblastic leukemias, thyroid carcinoma and other human tumors, BAG3 expression sustains cell survival and impairs cell response to therapy. This review discusses two patents concerning, respectively, BAG3 and other Hsc70/Hsp70 co-chaperones, namely HspBP-1 and HspBP-2. © 2009 Bentham Science Publishers Ltd

BAG3 Protein: Role in Some Neoplastic Cell Types and Identification as a Candidate Target for Therapy

Neoplasia pathogenesis and resistance to therapy are largely determined by acquired resistance to apoptosis. Among apoptosis- regulating molecules, a role is emerging for BAG3, a member of the BAG co-chaperone protein family. Through its bag, WW and prolix-rich domains, BAG3 protein can interact with a variety of molecular partners, including Hsc70/Hsp70, phospholipase C- gamma and others. It has been recently shown that, in human primary lymphoid and myeloblastic leukemias, thyroid carcinoma and other human tumours, BAG3 expression sustains cell survival and impairs cell response to therapy. Here we summarize findings that assign to BAG3 an anti-apoptotic role in some neoplastic cell types, in addition to other biological activities, and identify the protein as a candidate target of therapy

BAG3 regulates formation of the SNARE complex and insulin secretion

Insulin release in response to glucose stimulation requires exocytosis of insulin-containing granules. Glucose stimulation of beta cells leads to focal adhesion kinase (FAK) phosphorylation, which acts on the Rho family proteins (Rho, Rac and Cdc42) that direct F-actin remodeling. This process requires docking and fusion of secretory vesicles to the release sites at the plasma membrane and is a complex mechanism that is mediated by SNAREs. This transiently disrupts the F-actin barrier and allows the redistribution of the insulin-containing granules to more peripheral regions of the β cell, hence facilitating insulin secretion. In this manuscript, we show for the first time that BAG3 plays an important role in this process. We show that BAG3 downregulation results in increased insulin secretion in response to glucose stimulation and in disruption of the F-actin network. Moreover, we show that BAG3 binds to SNAP-25 and syntaxin-1, two components of the t-SNARE complex preventing the interaction between SNAP-25 and syntaxin-1. Upon glucose stimulation BAG3 is phosphorylated by FAK and dissociates from SNAP-25 allowing the formation of the SNARE complex, destabilization of the F-actin network and insulin release

Role of BAG3 protein in leukemia cell survival and response to therapy.

The ability of BAG3, a member of the BAG family of heat shock protein (Hsp) 70 - cochaperones, to sustain the survival of human primary B-CLL and ALL cells was recognized about nine years ago. Since then, the anti-apoptotic activity of BAG3 has been confirmed in other tumor types, where it has been shown to regulate the intracellular concentration and localization of apoptosis-regulating factors, including NF-κB-activating (IKKγ) and Bcl2-family (Bax) proteins. Furthermore, growing evidences support its role in lymphoid and myeloid leukemia response to therapy. Moreover in the last years, the contribution of BAG3 to autophagy, a process known to be involved in the pathogenesis and response to therapy of leukemia cells, has been disclosed, opening a new avenue for the interpretation of the role of this protein in leukemias' biology

BAG3 protein regulates cell-survival in childhood acute lymphoblastic leukemia cells.

Letter to the Edito

BAG3 Protein Is Over-Expressed in Endometrioid Endometrial Adenocarcinomas

Endometrioid endometrial cancer is the most common gynaecological tumor in developed countries, and its incidence is increasing. The definition of subtypes, based on clinical and endocrine features or on histopathological characteristics, correlate to some extent with patient's prognosis, but there is substantial heterogeneity within tumor types. The search for molecules and mechanisms implied in determining the progression and the response to therapy for this cancer is still ongoing. BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumor types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby, modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. BAG3 expression in human endometrial cancer tissues was not investigated so far. Here, we show that BAG3 protein levels are elevated in tumoral and hyperplastic cells in respect to normal glands. Furthermore, BAG3 subcellular localization appears to be changed in tumoral compared to normal cells. Our results indicate a possible role for BAG3 protein in the maintenance of cell survival in endometrioid endometrial cancer and suggest that this field of studies is worthy of further investigations. J. Cell. Physiol. 232: 309–311, 2017. © 2016 Wiley Periodicals, Inc