The Interaction of the Tumor Suppressor FAM46C with p62 and FNDC3 Proteins Integrates Protein and Secretory Homeostasis

Fucci, Chiara; Resnati, Massimo; Riva, E.; Perini, Tommaso; Ruggieri, Elena; Orfanelli, Ugo; Paradiso, Francesca; Cremasco, Floriana; Raimondi, Andrea; Pasqualetto, Elena; Rampoldi, Luca; Cenci, Simone; Milan, Enrico

doi:10.1016/j.celrep.2020.108162

Cited by 32 publications

(60 citation statements)

References 73 publications

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“…Accordingly, both TENT5A and TENT5C are clearly associated with membranes (Figure S6B; Bilska et al, 2020). TENT5C association with the ER was also recently confirmed by others, and the mechanism of such association was proposed (Fucci et al, 2020;Manfrini et al, 2020). TENT5 substrates do not harbor any detectable specific sequence motives and represent very abundant mRNAs, suggesting that the mechanism determining substrate specificity relies on localization rather than sequence recognition.…”

Section: Discussionsupporting

confidence: 70%

Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

et al. 2021

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Osteoblasts orchestrate bone formation through the secretion of type I collagen and other constituents of the matrix on which hydroxyapatite crystals mineralize. Here, we show that TENT5A, whose mutations were found in congenital bone disease osteogenesis imperfecta patients, is a cytoplasmic poly(A) polymerase playing a crucial role in regulating bone mineralization. Direct RNA sequencing revealed that TENT5A is induced during osteoblast differentiation and polyadenylates mRNAs encoding Col1a1, Col1a2, and other secreted proteins involved in osteogenesis, increasing their expression. We postulate that TENT5A, possibly together with its paralog TENT5C, is responsible for the wave of cytoplasmic polyadenylation of mRNAs encoding secreted proteins occurring during bone mineralization. Importantly, the Tent5a knockout (KO) mouse line displays bone fragility and skeletal hypomineralization phenotype resulting from quantitative and qualitative collagen defects. Thus, we report a biologically relevant posttranscriptional regulator of collagen production and, more generally, bone formation.

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Section: Discussionsupporting

confidence: 70%

Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

et al. 2021

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“…Furthermore, FAM46C that encodes a non-canonical poly(A) polymerase is mutated in almost 20% of MM patients. FAM46C sustains ER biogenesis in MM cells and this activity is controlled by autophagy through an inhibitory interaction with SQSTM1 [211]. This SQSTM1/FAM46C interplay could be exploited to increase PI efficacy and alleviate PI resistance.…”

Section: Autophagy and Ferroptosis Are Forms Of Death Controlled By MM Metabolismmentioning

confidence: 99%

Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

Caillot

Dakik

Mazurier

et al. 2021

Cancers

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Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse underlying the need of new therapeutic approaches. Plasma cells are prone to produce large amounts of immunoglobulins causing the production of intracellular ROS. Although adapted to high level of ROS, MM cells die when exposed to drugs increasing ROS production either directly or by inhibiting antioxidant enzymes. In this review, we discuss the efficacy of ROS-generating drugs for inducing MM cell death and counteracting acquired drug resistance specifically toward proteasome inhibitors.

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“…Further mechanistic study revealed that abrogation of bortezomib-induced apoptosis is partially mediated through inhibition of transcription factor Nrf2-associated downstream signaling that increases the GSH pool through upregulation of the xCT subunit of the Xc- cystine-glutamate antiporter [ 128 ]. A recent study revealed that FAM46C, one of the most recurrently mutated genes in MM, promotes ER expansion and augments immunoglobulin secretion, thus leading to a remarkable increase in oxidative stress that goes beyond the cellular capacity to maintain sustained proteostasis [ 129 ]. These findings are in line with previous research indicating that loss of oncosuppressive FAM46C confers a survival advantage to MM cells and poor prognosis in MM patients [ 130 , 131 ].…”

Section: Modulation Of Oxidative Stress In Multiple Myelomamentioning

confidence: 99%

Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

Xiong

Chng

Zhou

2021

Cell. Mol. Life Sci.

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Under physiological and pathological conditions, cells activate the unfolded protein response (UPR) to deal with the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. Multiple myeloma (MM) is a hematological malignancy arising from immunoglobulin-secreting plasma cells. MM cells are subject to continual ER stress and highly dependent on the UPR signaling activation due to overproduction of paraproteins. Mounting evidence suggests the close linkage between ER stress and oxidative stress, demonstrated by overlapping signaling pathways and inter-organelle communication pivotal to cell fate decision. Imbalance of intracellular homeostasis can lead to deranged control of cellular functions and engage apoptosis due to mutual activation between ER stress and reactive oxygen species generation through a self-perpetuating cycle. Here, we present accumulating evidence showing the interactive roles of redox homeostasis and proteostasis in MM pathogenesis and drug resistance, which would be helpful in elucidating the still underdefined molecular pathways linking ER stress and oxidative stress in MM. Lastly, we highlight future research directions in the development of anti-myeloma therapy, focusing particularly on targeting redox signaling and ER stress responses.

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The Interaction of the Tumor Suppressor FAM46C with p62 and FNDC3 Proteins Integrates Protein and Secretory Homeostasis

Cited by 32 publications

References 73 publications

Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

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