Disease relevance of NUMA1

• Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha [1].
• A nonsynonymous SNP (A794G) in NuMA was identified that showed a stronger association with breast cancer risk than the initial marker SNP (OR=2.8, P=0.005 initial sample; OR=2.1, P=0.002 combined) [2].
• Analysis of the cDNA sequences of various clones, coupled with polymerase chain reaction amplification of cellular mRNA and genomic Southern blotting with region-specific probes, all indicated that multiple mRNA species were present in U-251 human glioma cells, derived from alternative splicing of the RNA transcript from a single NuMA/W1 gene [3].
• NuMA and nuclear lamins are cleaved during viral infection--inhibition of caspase activity prevents cleavage and rescues HeLa cells from measles virus-induced but not from rhinovirus 1B-induced cell death [4].
• HeLa cells were infected with human rhinovirus 1B (HRV 1B) or measles virus (MV), and Nuclear Mitotic Apparatus protein (NuMA) and lamins A/C and B were used as markers for internal nuclear matrix and peripheral nuclear lamina, respectively [4].

Psychiatry related information on NUMA1

• We tested this prediction in the mammalian mitotic extract and, consistent with the model, found that increasing the contribution of microtubule cross-linking by NuMA compensated for the loss of Eg5 motor activity [5].

High impact information on NUMA1

• During mitosis, LGN recruits NuMA to the cell cortex, while cortical association of LGN itself requires the C-terminal Galpha binding domain [6].
• Overexpression of Galphai or YFP-LGN causes a pronounced oscillation of metaphase spindles, and NuMA binding to LGN is required for these spindle movements [6].
• We have characterized a fourth APL gene fusion, which links exons encoding the retinoic acid and DNA-binding domains of RARA to 5' exons of NuMA, a gene that encodes the nuclear mitotic apparatus protein [7].
• Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia [7].
• Its association with the nuclear matrix and its localization during mitosis to the site of nuclear reassembly suggest the interesting possibility that NuMA protein could be representative of a class of proteins involved in the early events of nuclear reassembly [8].

Chemical compound and disease context of NUMA1

• We further investigated the presence of NuMA in a cultured estrogen-dependent human breast cancer cell line and observed the disappearance of nuclear NuMA in the quiescent cells [9].

Biological context of NUMA1

• We found that LGN binds the nuclear mitotic apparatus protein NuMA, which tethers spindles at the poles, and that this interaction is required for the LGN phenotype [10].
• NuMA and 4.1R partially colocalize in the interphase nucleus of MDCK cells and redistribute to the spindle poles early in mitosis [11].
• Overexpression of a 135-kD isoform of 4.1R alters the normal distribution of NuMA in the interphase nucleus [11].
• The minimal sequence sufficient for this interaction has been mapped to the amino acids encoded by exons 20 and 21 of 4.1R and residues 1788-1810 of NuMA [11].
• We discuss our result in terms of a model where PARsylation of NuMA by tankyrase 1 in mitosis could play a role in sister telomere separation and/or mitotic progression [12].

Anatomical context of NUMA1

• Similar to NuMA, a significant amount of cohesin was found to associate with the nuclear matrix [13].
• The large coiled-coil protein NuMA plays an essential role in organizing microtubule minus ends at spindle poles in vertebrate cells [14].
• In interphase cells NuMA protein is restricted to the nucleus and is a constituent of isolated nuclear matrices, but in mitotic cells it is observed by indirect immunofluorescence microscopy to be concentrated at the polar regions of the mitotic apparatus [8].
• Immunofluorescence studies of this hybrid cell showed that the distribution of NuMA protein is equivalent to that in human cells [8].
• Upon nuclear envelope breakdown, large cytoplasmic aggregates of green fluorescent protein (GFP)-tagged NuMA stream poleward along spindle fibers in association with the actin-related protein 1 (Arp1) protein of the dynactin complex and cytoplasmic dynein [15].

Associations of NUMA1 with chemical compounds

• Perturbation of histone acetylation in the acini by trichostatin A treatment altered chromatin structure, disrupted NuMA foci, and induced cell proliferation [16].
• After induction of a 180 kDa form of NuMA in interphase HeLa cells by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, nuclear apoptotic phenomena including chromatin condensation, DNA fragmentation, and micronucleation were observed [17].
• When HL60 cells were stimulated by diverse apoptosis inducers such as camptothecin, staurosporine, cycloheximide, and A23187, the extent of NuMA cleavage to produce a 180 kDa product was comparable with the degree of oligonucleosomal laddering [17].
• While none of these specific mutations in the NuMA sequence alters the faithful targeting of the protein into the interphase nucleus, mutation of threonine residue 2040 alone or in combination with mutations in other potential p34cdc2 phosphorylation sites abolishes NuMA's ability to associate normally with the microtubules of the mitotic spindle [18].
• In addition three peptides derived from immunoprecipitated human SPN by cyanogen bromide cleavage and covering more than fifty amino acids show a perfect fit with the sequence predicted for NuMA protein [19].

Physical interactions of NUMA1

• A nonerythroid isoform of protein 4.1R interacts with the nuclear mitotic apparatus (NuMA) protein [11].
• Protein 4.1N binding to nuclear mitotic apparatus protein in PC12 cells mediates the antiproliferative actions of nerve growth factor [20].

Regulatory relationships of NUMA1

• Using this assay, we show that protein kinase activity and the NuMA-binding protein LGN regulate the dynamic exchange of NuMA on microtubule asters [14].

Other interactions of NUMA1

• We also found that 4.1G, a ubiquitous homolog of 4.1R, is present in mutated as well as control cells and that its C-terminal region binds efficiently to NuMA, suggesting that in fact mitotic spindles host a mixture of the two 4.1 family members [21].
• Mammalian Pins is a conformational switch that links NuMA to heterotrimeric G proteins [6].
• NuMA transport is required for spindle pole assembly and maintenance, since disruption of the dynactin complex (by increasing the amount of the dynamitin subunit) or dynein function (with an antibody) strongly inhibits NuMA translocation and accumulation and disrupts spindle pole assembly [15].
• Overexpression of the C-terminal tail of Lgl2 induced mis-localization of the nuclear mitotic apparatus protein NuMA and disorganization of the mitotic spindle during mitosis, eventually causing formation of multiple micronuclei [22].
• In contrast, cases with t(11;17)(q13;q21) and t(5;17)(q35;q21) which fuse RARA with NuMA and NPM, respectively, were reported to be sensitive to ATRA [23].

Analytical, diagnostic and therapeutic context of NUMA1

• We showed by immunofluorescence and immunoprecipitation that association between tankyrase 1 and NuMA increases dramatically at the onset of mitosis, concomitant with PARsylation of NuMA [12].
• Using a FRET biosensor, we find that LGN behaves as a conformational switch: in its closed state, the N and C termini interact, but NuMA or Galphai can disrupt this association, allowing LGN to interact simultaneously with both proteins, resulting in their cortical localization [6].
• Immunoprecipitations and gel filtration demonstrate the assembly of a reversible, mitosis-specific complex of NuMA with dynein and dynactin [15].
• In vitro GAS41 bound to the C-terminal part of the rod region of NuMA, as shown by dot overlay and by surface plasmon resonance measurements [24].
• Immunoprecipitation studies demonstrated that overexpressed Arp1alpha interacts with dynactin and NuMA proteins in cell extracts, and that these interactions are destabilized in the Arp1alpha mutants [25].

1. Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha. Sukhai, M.A., Wu, X., Xuan, Y., Zhang, T., Reis, P.P., Dubé, K., Rego, E.M., Bhaumik, M., Bailey, D.J., Wells, R.A., Kamel-Reid, S., Pandolfi, P.P. Oncogene (2004)
2. Association of the NuMA region on chromosome 11q13 with breast cancer susceptibility. Kammerer, S., Roth, R.B., Hoyal, C.R., Reneland, R., Marnellos, G., Kiechle, M., Schwarz-Boeger, U., Griffiths, L.R., Ebner, F., Rehbock, J., Cantor, C.R., Nelson, M.R., Braun, A. Proc. Natl. Acad. Sci. U.S.A. (2005)
3. Nuclear proteins of the bovine esophageal epithelium. II. The NuMA gene gives rise to multiple mRNAs and gene products reactive with monoclonal antibody W1. Tang, T.K., Tang, C.J., Chen, Y.L., Wu, C.W. J. Cell. Sci. (1993)
4. NuMA and nuclear lamins are cleaved during viral infection--inhibition of caspase activity prevents cleavage and rescues HeLa cells from measles virus-induced but not from rhinovirus 1B-induced cell death. Taimen, P., Berghäll, H., Vainionpää, R., Kallajoki, M. Virology (2004)
5. A mechanistic model for the organization of microtubule asters by motor and non-motor proteins in a mammalian mitotic extract. Chakravarty, A., Howard, L., Compton, D.A. Mol. Biol. Cell (2004)
6. Mammalian Pins is a conformational switch that links NuMA to heterotrimeric G proteins. Du, Q., Macara, I.G. Cell (2004)
7. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Wells, R.A., Catzavelos, C., Kamel-Reid, S. Nat. Genet. (1997)
8. Human-specific nuclear protein that associates with the polar region of the mitotic apparatus: distribution in a human/hamster hybrid cell. Lydersen, B.K., Pettijohn, D.E. Cell (1980)
9. Preferential expression of NuMA in the nuclei of proliferating cells. Taimen, P., Viljamaa, M., Kallajoki, M. Exp. Cell Res. (2000)
10. A mammalian Partner of inscuteable binds NuMA and regulates mitotic spindle organization. Du, Q., Stukenberg, P.T., Macara, I.G. Nat. Cell Biol. (2001)
11. A nonerythroid isoform of protein 4.1R interacts with the nuclear mitotic apparatus (NuMA) protein. Mattagajasingh, S.N., Huang, S.C., Hartenstein, J.S., Snyder, M., Marchesi, V.T., Benz, E.J. J. Cell Biol. (1999)
12. NuMA is a major acceptor of poly(ADP-ribosyl)ation by tankyrase 1 in mitosis. Chang, W., Dynek, J.N., Smith, S. Biochem. J. (2005)
13. A potential role for human cohesin in mitotic spindle aster assembly. Gregson, H.C., Schmiesing, J.A., Kim, J.S., Kobayashi, T., Zhou, S., Yokomori, K. J. Biol. Chem. (2001)
14. Multiple mechanisms regulate NuMA dynamics at spindle poles. Kisurina-Evgenieva, O., Mack, G., Du, Q., Macara, I., Khodjakov, A., Compton, D.A. J. Cell. Sci. (2004)
15. Formation of spindle poles by dynein/dynactin-dependent transport of NuMA. Merdes, A., Heald, R., Samejima, K., Earnshaw, W.C., Cleveland, D.W. J. Cell Biol. (2000)
16. Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus. Lelièvre, S.A., Weaver, V.M., Nickerson, J.A., Larabell, C.A., Bhaumik, A., Petersen, O.W., Bissell, M.J. Proc. Natl. Acad. Sci. U.S.A. (1998)
17. Dynamic changes of NuMA during the cell cycle and possible appearance of a truncated form of NuMA during apoptosis. Hsu, H.L., Yeh, N.H. J. Cell. Sci. (1996)
18. Mutation of the predicted p34cdc2 phosphorylation sites in NuMA impair the assembly of the mitotic spindle and block mitosis. Compton, D.A., Luo, C. J. Cell. Sci. (1995)
19. Microinjection of a monoclonal antibody against SPN antigen, now identified by peptide sequences as the NuMA protein, induces micronuclei in PtK2 cells. Kallajoki, M., Harborth, J., Weber, K., Osborn, M. J. Cell. Sci. (1993)
20. Protein 4.1N binding to nuclear mitotic apparatus protein in PC12 cells mediates the antiproliferative actions of nerve growth factor. Ye, K., Compton, D.A., Lai, M.M., Walensky, L.D., Snyder, S.H. J. Neurosci. (1999)
21. A splicing alteration of 4.1R pre-mRNA generates 2 protein isoforms with distinct assembly to spindle poles in mitotic cells. Delhommeau, F., Vasseur-Godbillon, C., Leclerc, P., Schischmanoff, P.O., Croisille, L., Rince, P., Morinière, M., Benz, E.J., Tchernia, G., Tamagnini, G., Ribeiro, L., Delaunay, J., Baklouti, F. Blood (2002)
22. Direct binding of Lgl2 to LGN during mitosis and its requirement for normal cell division. Yasumi, M., Sakisaka, T., Hoshino, T., Kimura, T., Sakamoto, Y., Yamanaka, T., Ohno, S., Takai, Y. J. Biol. Chem. (2005)
23. Atypical response to all-trans retinoic acid in a der(5)t(5;17) acute promyelocytic leukemia. Mozziconacci, M.J., Liberatore, C., Grignani, F., Sainty, D., Pelicci, P.G., Birg, F., Lafage-Pochitaloff, M. Leukemia (1999)
24. GAS41, a highly conserved protein in eukaryotic nuclei, binds to NuMA. Harborth, J., Weber, K., Osborn, M. J. Biol. Chem. (2000)
25. Overexpression of normal and mutant Arp1alpha (centractin) differentially affects microtubule organization during mitosis and interphase. Clark, I.B., Meyer, D.I. J. Cell. Sci. (1999)