Susceptibility to p53 dependent apoptosis correlates with increased levels of Gas2 and Gas3 proteins

Brancolini, Claudio; Marzinotto, Stefania; Schneider, Claudio

doi:10.1038/sj.cdd.4400232

Cited by 17 publications

(14 citation statements)

References 25 publications

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“…38,39 Susceptibility to p53-dependent apoptosis has been shown to be correlated with increased levels of Gas2 protein, possibly because of enhanced p53 stability and transcriptional activity. 38,40 Little is known about the biologic function of Gas2L3, 41 so we first confirmed its radiation-induced up-regulation in necdinnull HSPCs using quantitative PCR analysis ( Figure 7B). We hypothesized that up-regulation of Gas2L3 in irradiated necdinnull HSCs may account for their enhanced radiosensitivity and, indeed, found that the efficient knockdown of Gas2L3 expression decreased the radiation sensitivity of necdin-null LSK cells ( Figure 7C).…”

Section: Necdin Regulates Hspc Radio-/chemo-sensitivity 1607mentioning

confidence: 87%

Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells

Asai

Liu

Giandomenico

et al. 2012

Blood

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We recently defined a critical role for p53 in regulating the quiescence of adult hematopoietic stem cells (HSCs) and identified necdin as a candidate p53 target gene. Necdin is a growth-suppressing protein and the gene encoding it is one of several that are deleted in patients with Prader-Willi syndrome. To define the intrinsic role of necdin in adult hematopoiesis, in the present study, we transplanted necdin-null fetal liver cells into lethally irradiated recipients. We show that necdin-null adult HSCs are less quiescent and more proliferative than normal HSCs, demonstrating the similar role of necdin and p53 in promoting HSC quiescence during steady-state conditions. However, wild-type recipients repopulated with necdin-null hematopoietic stem/ progenitor cells show enhanced sensitivity to irradiation and chemotherapy, with increased p53-dependent apoptosis, myelosuppression, and mortality. Necdin controls the HSC response to genotoxic stress via both cell-cycle-dependent and cell-cycle-independent mechanisms, with the latter occurring in a Gas2L3-dependent manner. We conclude that necdin functions as a molecular switch in adult hematopoiesis, acting in a p53-like manner to promote HSC quiescence in the steady state, but suppressing p53-dependent apoptosis in response to genotoxic stress. (Blood. 2012;120(8): 1601-1612) IntroductionHematopoietic stem cells (HSCs) can remain quiescent or can enter the cell cycle and either self-renew or differentiate. 1 HSCs divide infrequently, and it has long been thought that the entire HSC pool turns over every few weeks and that HSCs regularly enter and exit the cell cycle. 1,2 This paradigm has been challenged, because 2 functionally distinct HSC populations, dormant HSCs and activated HSCs, have been identified by independent groups of investigators. 3,4 HSC quiescence is likely controlled by both HSC-intrinsic mechanisms and BM microenvironmental factors, with several genes and signaling pathways implicated in this process. 5 Several regulators of the cell-cycle machinery have been shown to play critical regulatory roles in hematopoietic stem/progenitor cell (HSPC) proliferation, including p21, p57, p18, and the D-type cyclins and their catalytic partners Cdk4 and Cdk6. 6-10 HSC cell-fate decisions are also regulated by several transcription factors (eg, Gfi-1, MEF/ELF4, Pbx-1, C-myc, and N-myc). [11][12][13][14] Interestingly, recent studies indicate that tumor-suppressor genes, including PTEN, pRb, PML, APC, and Fbw7, may also play critical roles in maintaining HSCs in a quiescent state. [15][16][17][18][19] In addition to HSC-intrinsic mechanisms, HSC function is regulated by ligand-receptor interactions, including angiopoietin and Tie-2, thrombopoietin and c-Mpl, SCF and c-Kit, and stromal-derived factor 1 (also known as Cxcl12) and Cxcr4. [20][21][22][23] Recently, we defined a critical role for p53 in regulating HSC quiescence and identified necdin as a p53 target gene with a promoter that binds and is transactivated by p53. 24,25 Necdin is a growth-suppressing ...

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Section: Necdin Regulates Hspc Radio-/chemo-sensitivity 1607mentioning

confidence: 87%

Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells

Asai

Liu

Giandomenico

et al. 2012

Blood

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“…PMP22, also known as CD25, has been associated with fibroblast apoptosis [8]. It is also expressed in myelinating Schwann cells where it plays a role in differentiation [9-11].…”

Section: Introductionmentioning

confidence: 99%

MP20, the second most abundant lens membrane protein and member of the tetraspanin superfamily, joins the list of ligands of galectin-3

et al. 2001

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Background: Although MP20 is the second most highly expressed membrane protein in the lens its function remains an enigma. Putative functions for MP20 have recently been inferred from its assignment to the tetraspanin superfamily of integral membrane proteins. Members of this family have been shown to be involved in cellular proliferation, differentiation, migration, and adhesion. In this study, we show that MP20 associates with galectin-3, a known adhesion modulator.

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“…Studies in cultured cells have demonstrated that Gas3/PMP22 can regulate cell death and cell spreading both in fibroblasts and Schwann cells (Fabbretti et al, 1995;Brancolini et al, 1997;Zoidl et al, 1997;Baudet et al, 1998). The effect on cell spreading was dependent on the small GTPase Rho since the coexpression of activated Rho or the treatment of the cells with bacterial toxins regulating Rho GTP status can modulate the Gas3/PMP22-dependent effect on cell spreading .…”

Section: Introductionmentioning

confidence: 99%

Exposure at the Cell Surface Is Required for Gas3/PMP22 To Regulate Both Cell Death and Cell Spreading: Implication for the Charcot–Marie–Tooth Type 1A and Dejerine–Sottas Diseases

Brancolini

Edomi

Marzinotto

et al. 2000

MBoC

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Gas3/PMP22 is a tetraspan membrane protein highly expressed in myelinating Schwann cells. Point mutations in thegas3/PMP22 gene account for the dominant inherited peripheral neuropathies Charcot–Marie–Tooth type 1A disease (CMT1A) and Dejerine–Sottas syndrome (DSS). Gas3/PMP22 can regulate apoptosis and cell spreading in cultured cells.Gas3/PMP22 point mutations, which are responsible for these diseases, are defective in this respect. In this report, we demonstrate that Gas3/PMP22-WT is exposed at the cell surface, while its point-mutated derivatives are intracellularly retained, colocalizing mainly with the endoplasmic reticulum (ER). The putative retrieval motif present in the carboxyl terminus of Gas3/PMP22 is not sufficient for the intracellular sequestration of its point-mutated forms. On the contrary, the introduction of a retrieval signal at the carboxyl terminus of Gas3/PMP22-WT leads to its intracellular accumulation, which is accompanied by a failure to trigger cell death as well as by changes in cell spreading. In addition, by substituting the Asn at position 41 required for N-glycosylation, we provide evidence that N-glycosylation is required for the full effect on cell spreading, but it is not necessary for triggering cell death. In conclusion, we suggest that the DSS and the CMT1A neuropathies derived from point mutations ofGas3/PMP22 might arise, at the molecular level, from a reduced exposure of Gas3/PMP22 at the cell surface, which is required to exert its biological functions.

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Susceptibility to p53 dependent apoptosis correlates with increased levels of Gas2 and Gas3 proteins

Cited by 17 publications

References 25 publications

Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells

Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells

MP20, the second most abundant lens membrane protein and member of the tetraspanin superfamily, joins the list of ligands of galectin-3

Exposure at the Cell Surface Is Required for Gas3/PMP22 To Regulate Both Cell Death and Cell Spreading: Implication for the Charcot–Marie–Tooth Type 1A and Dejerine–Sottas Diseases

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