Other entities represented in this entry:
HGNC Approved Gene Symbol: NUMA1
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:72,002,864-72,080,542 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.4 | Leukemia, acute promyelocytic, somatic | 612376 | 3 |
The NUMA protein was one of the first to be described as a cell cycle-related protein based on a distinct immunofluorescent staining pattern: in interphase, NUMA is present throughout the nucleus, and in mitosis, it localizes to the spindle apparatus (Lydersen and Pettijohn, 1980). Some patients with autoimmune disease have antibodies directed against the NUMA protein. The full-length NUMA cDNA (Compton et al., 1992; Yang et al., 1992) predicts a protein with a calculated molecular mass of about 237 kD, containing 2 globular domains separated by a coiled-coil domain of 1,485 amino acids. Wong et al. (2006) stated that the coiled-coil region of NUMA can form parallel coiled-coil dimers.
Using double-immunofluorescence experiments, Yang et al. (1992) found that NUMA dissociated from condensing chromosomes during early prophase, before the complete disintegration of the nuclear lamina. As mitosis progressed, NUMA reassociated with telophase chromosomes. Compton et al. (1992) found that NUMA associated with the spindle immediately upon nuclear envelope breakdown and progressed down the spindle microtubules to concentrate at the pericentrosomal region. At the completion of anaphase, NUMA dissociated from spindle microtubules and was imported into the regenerating nuclei through nuclear pores.
The guanosine triphosphatase Ran (601179) stimulates assembly of microtubule asters and spindles in mitotic Xenopus egg extracts. A carboxy-terminal region of NUMA, a nuclear protein required for organizing mitotic spindle poles, mimics Ran's ability to induce asters (Merdes et al., 1996). This NUMA fragment also specifically interacts with the nuclear transport factor, importin-beta (602738). Wiese et al. (2001) showed that importin-beta is an inhibitor of microtubule aster assembly in Xenopus egg extracts and that Ran regulates the interaction between importin-beta and NUMA. Importin-beta therefore links NUMA to regulation by Ran. Wiese et al. (2001) concluded that this suggests that similar mechanisms regulate nuclear import during interphase and spindle assembly during mitosis.
Quintyne et al. (2005) described a process of centrosomal clustering that prevented the formation of multipolar spindles in noncancer cells. Noncancer cells needed to overcome this clustering mechanism to allow multipolar spindles to form at a high frequency. The microtubule motor cytoplasmic dynein (see 600112) was a critical part of this coalescing machinery, and in some tumor cells overexpression of the spindle protein NUMA interfered with dynein localization, promoting multipolarity.
Wong et al. (2006) stated that RAE1 (603343) also binds to microtubules and that either lowering RAE1 levels or increasing NUMA levels results in spindle abnormalities. They found that either simultaneous depletion of RAE1 and NUMA levels or simultaneous overexpression of RAE1 and NUMA levels rescued spindle bipolarity. RAE1 and NUMA formed a transient complex during mitosis in HeLa cells, and the binding of RAE1 to NUMA converted the NUMA dimer to a tetravalent crosslinker of microtubules. RAE1 interacted with a GLEBS-like motif at the N-terminal end of the coiled-coil domain of NUMA. Wong et al. (2006) concluded that a balance of these 2 proteins is required for bipolar spindle formation.
Using in vivo skin-specific lentiviral RNA interference, Williams et al. (2011) investigated spindle orientation regulation and provided direct evidence that LGN (609245), NuMA, and dynactin (DCTN1; 601143) are involved. In compromising asymmetric cell divisions, Williams et al. (2011) uncovered profound defects in stratification, differentiation, and barrier formation, and implicated Notch (190198) signaling as an important effector. Williams et al. (2011) concluded that asymmetric cell division components act by reorientating mitotic spindles to achieve perpendicular divisions, which in turn promote stratification and differentiation. Furthermore, the resemblance between their knockdown phenotypes and Rbpj (147183) loss-of-function mutants provided important clues that suprabasal Notch signaling is impaired when asymmetric cell divisions do not occur.
By fluorescence in situ hybridization, Sparks et al. (1993) demonstrated that the NUMA1 gene is present in single copy and located on chromosome 11q13.
Acute promyelocytic leukemia (APL; 612376) is uniquely associated with chromosomal translocations that disrupt the gene encoding the retinoic acid receptor, RARA (180240). In more than 99% of cases, this disruption results in the formation of a fusion of the RARA gene with the PML gene (102578). In rare variants of APL, the RARA gene has been found to be fused to 1 of 2 other genes, PLZF (176797) and NPM (164040). Although RARA dysregulation is evidently important in APL, the role of the various fusion partners is unclear. Wells et al. (1997) characterized a fourth APL gene fusion, which linked exons encoding the retinoic acid and DNA-binding domains of RARA to 5-prime exons of NUMA1. The NUMA/RARA fusion protein existed in sheet-like nuclear aggregates with which normal NUMA partly colocalized. In contrast to t(15;17) APL (the usual variety) the intracellular distribution of PML was normal in these cells. Wells et al. (1997) suggested that interference with retinoid signaling, and not disruption of PML organization, is essential to the APL phenotype. Their work implicated for the first time an element of the mitotic apparatus in the molecular pathogenesis of human malignancy. The proband of their study was a Caucasian male first seen at 6 months of age for investigation of multiple cutaneous lesions. Despite this unusual clinical presentation, peripheral blood morphology and cell-surface immunophenotype were typical of APL. Routine analysis of diagnostic bone marrow revealed a clonal cytogenetic abnormality, t(11;17)(q13;q21). The patient was treated with all-trans retinoic acid and achieved complete remission; he remained in morphologic remission 38 months after autologous bone marrow transplantation.
Compton, D. A., Szilak, I., Cleveland, D. W. Primary structure of NuMA, an intranuclear protein that defines a novel pathway for segregation of proteins at mitosis. J. Cell Biol. 116: 1395-1408, 1992. [PubMed: 1541636] [Full Text: https://doi.org/10.1083/jcb.116.6.1395]
Lydersen, B. K., Pettijohn, D. E. Human-specific nuclear protein that associates with the polar region of the mitotic apparatus: distribution in a human/hamster hybrid cell. Cell 22: 489-499, 1980. [PubMed: 7004645] [Full Text: https://doi.org/10.1016/0092-8674(80)90359-1]
Merdes, A., Ramyar, K., Vechio, J. D., Cleveland, D. W. A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly. Cell 87: 447-458, 1996. [PubMed: 8898198] [Full Text: https://doi.org/10.1016/s0092-8674(00)81365-3]
Quintyne, N. J., Reing, J. E., Hoffelder, D. R., Gollin, S. M., Saunders, W. S. Spindle multipolarity is prevented by centrosomal clustering. Science 307: 127-129, 2005. [PubMed: 15637283] [Full Text: https://doi.org/10.1126/science.1104905]
Sparks, C. A., Bangs, P. L., McNeil, G. P., Lawrence, J. B., Fey, E. G. Assignment of the nuclear mitotic apparatus protein NuMA gene to human chromosome 11q13. Genomics 17: 222-224, 1993. [PubMed: 8406455] [Full Text: https://doi.org/10.1006/geno.1993.1307]
Wells, R. A., Catzavelos, C., Kamel-Reid, S. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nature Genet. 17: 109-113, 1997. [PubMed: 9288109] [Full Text: https://doi.org/10.1038/ng0997-109]
Wiese, C., Wilde, A., Moore, M. S., Adam, S. A., Merdes, A., Zheng, Y. Role of importin-beta in coupling Ran to downstream targets in microtubule assembly. Science 291: 653-656, 2001. [PubMed: 11229403] [Full Text: https://doi.org/10.1126/science.1057661]
Williams, S. E., Beronja, S., Pasolli, H. A., Fuchs, E. Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470: 353-358, 2011. [PubMed: 21331036] [Full Text: https://doi.org/10.1038/nature09793]
Wong, R. W., Blobel, G., Coutavas, E. Rae1 interaction with NuMA is required for bipolar spindle formation. Proc. Nat. Acad. Sci. 103: 19783-19787, 2006. [PubMed: 17172455] [Full Text: https://doi.org/10.1073/pnas.0609582104]
Yang, C. H., Lambie, E. J., Snyder, M. NuMA: an unusually long coiled-coil related protein in the mammalian nucleus. J. Cell Biol. 116: 1303-1317, 1992. [PubMed: 1541630] [Full Text: https://doi.org/10.1083/jcb.116.6.1303]