Analysis of the lethal interaction between the prune and Killer of prune mutations of Drosophila.

Biggs, Joseph R.; Tripoulas, Nick; Hersperger, Evelyn; Dearolf, Charles R.; Shearn, Allen

doi:10.1101/gad.2.10.1333

Cited by 137 publications

(90 citation statements)

References 20 publications

(15 reference statements)

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“…called K-pn (Killer of prune). It induces Drosophila lethality in a dominant manner when associated with a null mutation of the prune gene involved in the fly eye pigment synthesis (16). The K-pn mutation substitutes a serine for a proline in a surface loop, named for this reason the K-pn loop, that makes subunit contacts in the hexamer and plays an important part in the stability of the hexamers (17,18).…”

Section: /Ebi Data Bank With Accession Number(s) Y07604 (Nm23-h4 Cdnamentioning

confidence: 99%

The Human nm23-H4 Gene Product Is a Mitochondrial Nucleoside Diphosphate Kinase

Milon¹,

Meyer²,

Chiadmi³

et al. 2000

Journal of Biological Chemistry

132

129

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We demonstrate here the catalytic activity and subcellular localization of the Nm23-H4 protein, product of nm23-H4, a new member of the human nm23/nucleoside diphosphate (NDP) kinase gene family (Milon, L., Rousseau-Merck, M., Munier, A., Erent, M., Lascu, I., Capeau, J., and Lacombe, M. L. (1997) Hum. Genet. 99, 550 -557). Nm3-H4 was synthesized in escherichia coli as the fulllength protein and as a truncated form missing the Nterminal extension characteristic of mitochondrial targeting. The truncated form possesses NDP kinase activity, whereas the full-length protein is inactive, suggesting that the extension prevents enzyme folding and/or activity. X-ray crystallographic analysis was performed on active truncated Nm23-H4. Like other eukaryotic NDP kinases, it is a hexamer. Nm23-H4 naturally possesses a serine residue at position 129, equivalent to the K-pn mutation of the Drosophila NDP kinase. The x-ray structure shows that the presence of Ser 129 has local structural effects that weaken subunit interactions. Site-directed mutagenesis shows that the serine is responsible for the lability of Nm23-H4 to heat and urea treatment, because the S129P mutant is greatly stabilized. Examination of human embryonic kidney 293 cells transfected with green fluorescent protein fusions by confocal microscopy shows a specific mitochondrial localization of Nm23-H4 that was also demonstrated by Western blot analysis of subcellular fractions of these cells. Import into mitochondria is accompanied by cleavage of the N-terminal extension that results in NDP kinase activity. Submitochondrial fractionation indicates that Nm23-H4 is associated with mitochondrial membranes, possibly to the contact sites between the outer and inner membranes.

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Section: /Ebi Data Bank With Accession Number(s) Y07604 (Nm23-h4 Cdnamentioning

confidence: 99%

The Human nm23-H4 Gene Product Is a Mitochondrial Nucleoside Diphosphate Kinase

Milon¹,

Meyer²,

Chiadmi³

et al. 2000

Journal of Biological Chemistry

132

129

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“…The metabolic defects in the Prune¯y do not a ect viability or fertility, however, the homo-or hemizygous Prune mutant is lethal in the presence of a single copy of a gain-of-function mutation in the abnormal wing disc gene (awd), dubbed`Killer-of-Prune' (awd K-pn ). Thē ies die at the third larval instar stage, developing melanotic (pseudo) tumours (Orevi and Falk, 1975;Biggs et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas–a possible mechanism for altering the nm23-H1 activity

et al. 2001

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PRUNE, the human homologue of the Drosophila gene, is located in 1q21.3, a region highly ampli®ed in human sarcomas, malignant tumours of mesenchymal origin. Prune protein interacts with the metastasis suppressor nm23-H1, but shows impaired a nity towards the nm23-H1 S120G mutant associated with advanced neuroblastoma. Based on these observations, we previously suggested that prune may act as a negative regulator of nm23-H1 activity. We found ampli®cation of PRUNE in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant ®brous histiocytomas (MFH) as well as in the less malignant liposarcomas. PRUNE ampli®cation was generally accompanied by high mRNA and moderate to high protein levels. The sarcoma samples expressed nm23-H1 mostly at low or moderate levels, whereas mRNA and protein levels were moderate to high in breast carcinomas. For the more aggressive sarcoma subtypes, 9/13 patients with PRUNE ampli®cation developed metastases. A similar situation was observed in all breast carcinomas with ampli®cation of PRUNE. Infection of NIH3T3 cells with a PRUNE recombinant retrovirus increased cell proliferation. Possibly, ampli®-cation and overexpression of PRUNE has the same e ect in the tumours. We suggest that ampli®cation and overexpression of PRUNE could be a mechanism for inhibition of nm23-H1 activity that a ect the development or progression of these tumours. Oncogene (2001) 20, 6881 ± 6890.

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“…Subsequently, a high degree of sequence homology has been reported between nm23 and nucleoside diphosphate (NDP) kinase in several specieis, including humans, rats, insects and bacteria (Biggs et al, 1988;Kimura et al, 1990;MuniozDorado et al, 1990;Lacombe et al, 1990;Stahl et al, 1991;Hama et al, 1991;Urano et al, 1992). NDP kinase activity of nm23 protein has also been reported, indicating the identity of these two molecules (Urano et al, 1992a,b).…”

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confidence: 99%

Inverse association of nm23-H1 expression by colorectal cancer with liver metastasis

Yamaguchi

Urano²,

Fushida³

et al. 1993

Br J Cancer

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Summary The expression of nm23-H1 mRNA and protein was studied in colorectal cancers by Northern blotting and immunohistochemistry. All 21 colorectal cancers studied by Northern blotting had increased levels of nm23-H I mRNA relative to the adjacent normal colonic mucosa. Increased nm23-H I protein expression was also observed in all 36 colorectal cancer cases including those studied by Northern blotting. There was no significant correlation between nm23-HI expression and tumour histology, serosal invasion, lymphatic invasion, venous invasion, or lymph node metastasis. However, the expression of both mRNA and protein was significantly lower in tumours associated with liver metastasis than in those without such metastasis. These observations indicate that the nm23 gene may play a role in the suppression of liver metastasis of colorectal cancer.

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Analysis of the lethal interaction between the prune and Killer of prune mutations of Drosophila.

Cited by 137 publications

References 20 publications

The Human nm23-H4 Gene Product Is a Mitochondrial Nucleoside Diphosphate Kinase

The Human nm23-H4 Gene Product Is a Mitochondrial Nucleoside Diphosphate Kinase

Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas–a possible mechanism for altering the nm23-H1 activity

Inverse association of nm23-H1 expression by colorectal cancer with liver metastasis

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