Interplay between the antimetastatic nm23 and the Retinoblastoma-related Rb2/p130 genes in promoting neuronal differentiation of PC12 cells

Lombardi, Doug; Palescandolo, Emanuele; Giordano, Antonio; Paggi, Marco G.

doi:10.1038/sj.cdd.4400842

Cited by 30 publications

(17 citation statements)

References 34 publications

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“…High specific activity of the enzyme was reported in the brain (150 kU/kg of protein) (30 ), and its expression was highlighted in human brain (31,55 ). Forced expression of the murine gene coding for NDKA affects neuron proliferation and differentiation (56,57 ). NM23/NDKA has also been implicated in neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

PARK7 and Nucleoside Diphosphate Kinase A as Plasma Markers for the Early Diagnosis of Stroke

Allard¹,

Burkhard

Lescuyer³

et al. 2005

Clinical Chemistry

127

101

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Background: Plasma markers for stroke could be useful in diagnosis and prognosis and in prediction of response of stroke patients to therapy. PARK7 and nucleoside diphosphate kinase A (NDKA) are increased in human postmortem cerebrospinal fluid (CSF), a model of global brain insult, suggesting that measurement in CSF and, more importantly, in plasma may be useful as a biomarker of stroke. Methods: We used ELISA to measure PARK7 and NDKA in plasma in 3 independent European and North American retrospective studies encompassing a total of 622 stroke patients and 165 control individuals. Results: Increases in both biomarkers were highly significant, with sensitivities of 54%-91% for PARK7 and 70%-90% for NDKA and specificities of 80%-97% for PARK7 and 90%-97% for NDKA. The concentrations of both biomarkers increased within 3 h of stroke onset. Conclusions: PARK7 and NDKA may be useful plasma biomarkers for the early diagnosis of stroke. In addition, this study demonstrated the utility of analysis of postmortem CSF proteins as a first step in the discovery of plasma markers of ischemic brain injury.

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Section: Discussionmentioning

confidence: 99%

PARK7 and Nucleoside Diphosphate Kinase A as Plasma Markers for the Early Diagnosis of Stroke

Allard¹,

Burkhard

Lescuyer³

et al. 2005

Clinical Chemistry

127

101

View full text Add to dashboard Cite

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“…Subsequently, low expression of the NM23-H1 protein has been linked to increased metastatic potential in human breast carcinoma (2), hepatoma (3), and gastric carcinoma (4). NM23-H1 overexpression has been shown experimentally to inhibit the metastatic phenotype and/or promote differentiation in melanoma (5), breast carcinoma (6), and transformed neural cell lines (7,8). The human nm23-H1 gene is one of eight related NM23 family members identified to date (reviewed in Ref.…”

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confidence: 99%

The Metastasis Suppressor NM23-H1 Possesses 3′-5′ Exonuclease Activity

McCorkle

Kaetzel

2004

Journal of Biological Chemistry

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NM23-H1 belongs to a family of eight gene products in humans that have been implicated in cellular differentiation and development, as well as oncogenesis and tumor metastasis. We have defined NM23-H1 biochemically as a 3-5 exonuclease by virtue of its ability in stoichiometric amounts to excise single nucleotides in a stepwise manner from the 3 terminus of DNA. The activity is dependent upon the presence of Mg 2؉ , is most pronounced with single-stranded substrates or mismatched bases at the 3 terminus of double-stranded substrates, and is inhibited by both ATP and the incorporation of cordycepin, a 2-deoxyadenosine analogue, into the 3-terminal position. The 3-5 exonuclease activity was assigned to NM23-H1 by virtue of: 1) precise coelution of enzymatic activity with wild-type and mutant forms of NM23-H1 protein during purification by hydroxylapatite and gel filtration column high performance liquid chromatography and 2) significantly diminished activity exhibited by purified recombinant mutant forms of the proteins. Lysine 12 appears to play an important role in the catalytic mechanism, as evidenced by the significant reduction in 3-5 exonuclease activity resulting from a Lys 12 to glutamine substitution within the protein. 3-5 Exonucleases are believed to play an important role in DNA repair, a logical candidate function underlying the putative antimetastatic and oncogenic activities of NM23-H1.nm23-H1 was first classified as a metastasis suppressor gene on the basis of its reduced expression in several metastatic melanoma cell lines relative to nonmetastatic counterparts (1). Subsequently, low expression of the NM23-H1 protein has been linked to increased metastatic potential in human breast carcinoma (2), hepatoma (3), and gastric carcinoma (4). NM23-H1 overexpression has been shown experimentally to inhibit the metastatic phenotype and/or promote differentiation in melanoma (5), breast carcinoma (6), and transformed neural cell lines (7,8). The human nm23-H1 gene is one of eight related NM23 family members identified to date (reviewed in Ref. 9). Each exhibits nucleoside-diphosphate kinase (NDPK) 1 activity, catalyzing the transfer of ␥-phosphate between nucleoside triphosphate and nucleoside diphosphate via a "ping-pong" mechanism (10). NDPK activity does not appear to be relevant to metastasis suppression, however, as catalytically inactive mutants retain metastasis suppressor activity (11,12). In addition to NDPK, a number of other biological activities have been reported for NM23 proteins, some of which have been proposed to underlie metastasis suppression. Two spontaneous mutations in NM23-H1, a serine 120 to glycine (S120G) substitution seen frequently in aggressive neuroblastomas (13), and a proline 96 to serine mutation that corresponds to the killer of prune mutation (Kpn; P96S) in the Drosophila homologue of NM23 (awd), both result in loss of antimetastatic activity (14). Interestingly, both mutations also abrogate a histidine-dependent protein kinase activity of NM23-H1 (15). This activity has ...

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“…Similar findings have been reported for neural cell model systems and in Drosophila. [19][20][21][22] Our most difficult project, still ongoing, asks how Nm23 suppresses metastasis on a biochemical level. This is an abundant, sticky protein and I read a new protein:protein interaction or activity monthly in the journals.…”

Section: Biographical Informationmentioning

confidence: 99%

The Gift of Absorption Patricia S. Steeg

Steeg¹

2004

Cancer Biology & Therapy

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The Gift of Absorption I live, eat, sleep, research. I love my family, read voraciously and have a few hobbies. But most nights after dinner, I choose to go upstairs and log onto email to see what's new. I could go out into the backyard and plant another rosebush, but its too shaded and the bushes don't do well anyway. In earlier phases of my career when my kids were young, time demands were different. Now the kids are almost grown and I have this gift of freedom which I choose to spend hunched over a computer. To be absorbed in one's work is a blessing; how many people on this earth are bored by what they do? To completely jump into a project and lose track of time and surroundings are gifts. The subject might be an experiment that a postdoc is working on or a concept with which I have been struggling. Or it might be the problem of how to get government research to work a bit more efficiently. Minor successes in any of these areas are very satisfying. As one's career progresses, life is increasingly a series of meetings, and time to be absorbed in science is at a premium. BIOGRAPHICAL INFORMATIONI am from a working class part of Baltimore and the first of my family to attend college. I attended Towson State University in Baltimore, with a BS in Biology. My classes were split between field biology and cell biology. After graduation, it was just a matter of what type of job came along first. For three years I worked as an environmental consultant for engineering firms, doing environmental impact statements for roads, strip mines, parks. But the degree to which decisions were made politically angered me and I realized that this was not a good career. Plan B was to go back to school and see what I could contribute. Cancer was always on my mind. My cousin Cindy, a year older than I, died of oral cancer while I was in college. She had a "toothache" at 16, which turned into never-ending radiation, surgery and misery. I vowed to do something about it, and that vow helped to shape my future. My Ph.D. research was in cellular immunology at the University of Maryland under the direction of Joe Oppenheim, then at the National Institute for Dental Research (NIDR) at NIH. A quick postdoc with George Martin was completed at NIDR, and then a move to the Laboratory of Pathology at the National Cancer Institute (NCI). I've been there ever since.George was interested in basement membranes, which brought up the subject of tumor cell invasion and metastasis. How tumor cells metastasized seemed to be a question worth my effort. I modeled my work after a paper, in which differential colony hybridization was used to identify genes over-and under-expressed between serum-starved and serum-fed cells. Can we do the same between nonmetastatic and metastatic tumor cells? Expecting to find genes that were turned on in metastasis such as proteases and adhesion molecules, I was bewildered when the best candidate was turned off in the highly metastatic cell lines. The discovery of Rb as a tumor suppressor stimulated my thinking: if genes could ...

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Interplay between the antimetastatic nm23 and the Retinoblastoma-related Rb2/p130 genes in promoting neuronal differentiation of PC12 cells

Cited by 30 publications

References 34 publications

PARK7 and Nucleoside Diphosphate Kinase A as Plasma Markers for the Early Diagnosis of Stroke

PARK7 and Nucleoside Diphosphate Kinase A as Plasma Markers for the Early Diagnosis of Stroke

The Metastasis Suppressor NM23-H1 Possesses 3′-5′ Exonuclease Activity

The Gift of Absorption Patricia S. Steeg

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