ASNA1, an ATPase targeting tail-anchored proteins, regulates melanoma cell growth and sensitivity to cisplatin and arsenite

Hemmingsson, Oskar; Zhang, Youyi; Still, Maria; Naredi, Peter

doi:10.1007/s00280-008-0762-2

Cited by 22 publications

(31 citation statements)

References 26 publications

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“…In addition, a cisplatin resistant subline of ovarian carcinoma overexpresses ASNA1. This confirms earlier observations from human malignant melanoma T289 cells where ASNA1 downregulation resulted in increased sensitivity to arsenite and cisplatin, retarded growth and increased apoptosis (16). The cisplatin and arsenite hypersensitivity due to ASNA1 deficiency is of the same magnitude in ovarian carcinoma and malignant melanoma.…”

Section: Discussionsupporting

confidence: 80%

“…TA-proteins are involved in several central pathways necessary for normal cellular function. Consequently, downregulation of ASNA1 results in disparate phenotypes such as changed cellular morphology, decreased insulin secretion, retarded growth, increased apoptosis and increased chemosensitivity (14,16). Notably, ASNA1 deficient cells do not seem generally hypersensitive to stress since they are as resistant as wild-type to zinc chloride and other toxic metals beside antimonite, arsenite and platinum (11,16).…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemistry studies reveal ASNA1 expression in several types of normal tissues and cancers (13). Downregulation of ASNA1 results in growth arrest and increased arsenite sensitivity in Caenorhabditis elegans (11,14), embryonic lethality in mice (15), decreased insulin secretion (14) and retarded growth and increased apoptosis in humans (16). An explanation for such a diverse set of functions may lie in recent reports showing that ASNA1 mediates ER membrane insertion of tailanchored proteins (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…We have previously reported increased sensitivity to arsenite and cisplatin by downregulation of ASNA1 in a human melanoma cell line (16). Cisplatin and carboplatin are generally considered to share the same pharmacodynamic and pharmacokinetic pathways while oxaliplatin cytotoxicity and resistance is mediated by other mechanisms (20).…”

Section: Introductionmentioning

confidence: 99%

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Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA1

Hemmingsson

Nöjd²,

Kao³

et al. 2009

Oncol Rep

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Abstract. Platinating agents constitute the first line treatment for ovarian cancer but treatment failure is common because of intrinsic and acquired resistance. Cancer cells develop the RASP-phenotype (cross resistance against arsenite, antimonite and platinum) associated with decreased accumulation of cisplatin and arsenite. ASNA1 is a possible subunit of a transport system for cisplatin and arsenite due to homology to arsA, an ATPase in the E. coli ars-complex responsible for efflux of arsenite and antimonite. Eukaryotic ASNA1 is a targeting factor for membrane insertion of tail-anchored proteins involved in the secretory pathway and cellular stress responses. The purpose with this study was to evaluate if ASNA1 expression influenced cisplatin, carboplatin, oxaliplatin or arsenite sensitivity in ovarian cancer. Human ovarian cancer cell line 2008 was transfected with a sense or an antisense ASNA1 construct. ASNA1 downregulated and overexpressing clones were identified by Western blots. Cell growth and chemosensitivity was determined by the MTT assay. Downregulated ASNA1 expression was associated with retarded growth and increased sensitivity to cisplatin, carboplatin, oxaliplatin and arsenite whereas the cisplatin resistant 2008/ A overexpresses ASNA1. These observations support the hypothesis that ASNA1 is a target to overcome platinum resistance in ovarian cancer.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA1

Hemmingsson

Nöjd²,

Kao³

et al. 2009

Oncol Rep

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“…Get3 homologues had been implicated in a diverse set of functions now presumed to be linked to the correct localizations of TA proteins (9)(10)(11)(12). Get3 is a protein-targeting factor, analogous to the signal recognition particle (SRP), and, similar to SRP components (13), is not essential for viability in yeast; however, the cells are sensitive to a variety of stresses such as heat and metals (14).…”

mentioning

confidence: 99%

Model for eukaryotic tail-anchored protein binding based on the structure of Get3

Suloway

Chartron²,

Zaslaver³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

102

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The Get3 ATPase directs the delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (ER). TA-proteins are characterized by having a single transmembrane helix (TM) at their extreme C terminus and include many essential proteins, such as SNAREs, apoptosis factors, and protein translocation components. These proteins cannot follow the SRP-dependent co-translational pathway that typifies most integral membrane proteins; instead, posttranslationally, these proteins are recognized and bound by Get3 then delivered to the ER in the ATP dependent Get pathway. To elucidate a molecular mechanism for TA protein binding by Get3 we have determined three crystal structures in apo and ADP forms from Saccharomyces cerevisae (ScGet3-apo) and Aspergillus fumigatus (AfGet3-apo and AfGet3-ADP). Using structural information, we generated mutants to confirm important interfaces and essential residues. These results point to a model of how Get3 couples ATP hydrolysis to the binding and release of TA-proteins.ArsA ͉ crystallography ͉ Deviant Walker A ͉ Get pathway ͉ protein transport

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Generation of mice with conditional null allele for GdX/Ubl4A

Wang

Ren

et al. 2012

Genesis

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GdX (also named Ubl4A) is a house-keeping gene located on the X chromosome and encodes a protein harboring an ubiquitin-like domain in human and mouse. Although identified in 1988, the function of GdX remains unknown. To elucidate the role of GdX in vivo, we generated a conditional GdX knockout mouse in which Exon 2 was flanked by two loxP sites. We obtained viable and fertile mice with homozygous GdX(flox/flox) or GdX(flox/Y) allele. Germ-line transmission was confirmed by crossing the mouse bearing conditionally targeted allele with an EIIα-Cre transgenic mouse. GdX was successfully depleted in tissues of EIIα-Cre-GdX-null mice. GdX(-/-) and GdX(-/Y) mice are viable and exhibit normal development compared with wild-type littermates within 6 months during our observation. We also observed that GdX knockout male mice were functionally normal in the reproductive system where Ubl4B was specifically expressed. GdX(flox/flox) and GdX(flox/Y) conditional mice provide a tool for further tissue-specific function analysis of the GdX protein under different conditions.

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ASNA1, an ATPase targeting tail-anchored proteins, regulates melanoma cell growth and sensitivity to cisplatin and arsenite

Abstract: Reduced ASNA1 expression is associated with significant inhibition of cell growth, increased apoptosis and increased sensitivity to cisplatin and arsenite.

Cited by 22 publications

References 26 publications

Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA1

Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA1

Model for eukaryotic tail-anchored protein binding based on the structure of Get3

Generation of mice with conditional null allele for GdX/Ubl4A

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