Disease relevance of MAP4

• Adenovirus 2 E1B-55K protein relieves p53-mediated transcriptional repression of the survivin and MAP4 promoters [1].
• These techniques have revealed that thin processes extending from monkey kidney cells (TC-7), and those made by human neuroblastoma cells (IMR-32) in response to retinoic acid, are often deficient in MAP4 immunoreactivity [2].
• We reported that wild-type p53 induction by doxorubicin in C127 breast cancer cells repressed MAP4, decreased microtubule polymerization, and increased Vinca alkaloid sensitivity [3].
• The COOH-terminal MT binding domain of MAP4 was expressed in Escherichia coli as a glutathione transferase fusion protein and was injected into rabbits to produce an antiserum that was then affinity purified and shown to be monospecific for MAP4 [4].
• To address the significance of beta-tubulin and MAP4 alterations in childhood ALL, two CCRF-CEM-derived Vinca alkaloid resistant cell lines, VCR R (vincristine) and VLB100 (vinblastine), were examined [5].

Psychiatry related information on MAP4

• We suggest that different levels of MAP4 on microtubules may directly modulate microtubule dynamics within single cells, as well as other microtubule functions such as those involving microtubule motor activity [2].

High impact information on MAP4

• However, MAP-2, MAP-4, and tau have common repetitive microtubule-binding motifs [6].
• We report that trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), abrogates the ability of p53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin [7].
• Stabilizing factors include a large group of microtubule-associated proteins (MAPs; e.g. MAP4, XMAP215, XMAP230/XMAP4 and XMAP310) and the destabilizing factors are a growing family of proteins (e.g. Stathmin/Op18 and XKCM1) [8].
• Removal of MAP4 from microtubules in vivo produces no observable phenotype at the cellular level [4].
• Cells progressed to mitosis with morphologically normal spindles in the absence of MAP4 binding to MTs [4].

Biological context of MAP4

• Finally, we tested the effects of MAP4 phosphorylation on microtubule dynamics [9].
• Moreover, septin depletion increased the number of cells with abnormal nuclei, and this effect was blocked by gene silencing of MAP4 [10].
• This approach relies on the finding that overexpression of MAP4 alone stabilizes microtubules during all phases of the cell cycle in human leukemia cells, and causes a potent mitotic block and a dramatic, previously unobserved, phenotype characterized by large monoastral spindles [11].
• Interestingly, the tubulin-sequestering derivative suppressed the monoastral mitotic phenotype of MAP4 (i.e. coexpression facilitated the formation of functional spindles) [11].
• Evidence that pMAP4.245 encodes MAP4 sequences includes immunoabsorption of MAP4 antibodies with the pMAP4.245 fusion protein, as well as identity of protein sequences obtained from HeLa 210 kD MAP4 with amino acid sequences encoded by pMAP4.245 [12].

Anatomical context of MAP4

• In this study, we have investigated the mechanism by which p34cdc2 kinase associates with the microtubule cytoskeleton in primate tissue culture cells whose major MAP is known to be MAP4 [9].
• A polyclonal antiserum raised against a HeLa cell microtubule-associated protein of Mr 210,000 (210 kD MAP or MAP4), an abundant non-neuronal MAP, was used to isolate cDNA clones encoding MAP4 from a human fetal brain lambda gt11 cDNA expression library [12].
• Microtubule-associated protein 4 (MAP4) regulates assembly, protomer-polymer partitioning and synthesis of tubulin in cultured cells [13].
• Similar multimeric tubulin-binding domains in other proteins of the MAP2 class, including tau in axons and MAP4 in glial cells, may play the same role in the development and support of asymmetric cell morphology [14].
• To test the hypothesis that phosphorylation at these sites influences microtubule properties or cell cycle progression, we prepared stable cell lines that inducibly express versions of MAP4 in which phosphorylation of these two serines was prevented by their replacement with alanine, lysine, or glutamate residues (AA-, KK-, or EE-MAP4) [15].

Associations of MAP4 with chemical compounds

• Depolymerization of some of the cellular microtubules with nocodazole preferentially retained the microtubule localization of both cyclin B and MAP4 [9].
• A small, proline-rich region in the C-terminal half of MAP4 bound directly to a Sept 2:6:7 heterotrimer, and to the Sept2 monomer [10].
• We find that the MAP4 kinase PAK1 phosphorylates the amino terminus of MEKK1 on serine 67 [16].
• UV irradiation, bleomycin, and doxorubicin increased wild-type p53 expression and decreased MAP4 expression [17].
• Microinjection of the affinity purified Ab into human fibroblasts and monkey epithelial cells abolished MAP4 binding to MTs as assayed with a rat polyclonal antibody against the NH2-terminal projection domain of MAP4 [4].

Physical interactions of MAP4

• Non-neuronal 210 x 10(3) Mr microtubule-associated protein (MAP4) contains a domain homologous to the microtubule-binding domains of neuronal MAP2 and tau [12].

Regulatory relationships of MAP4

• In intact cells, MAP4 was required for the stabilization of microtubules induced by septin depletion [10].
• Expression of MAP4 is transcriptionally repressed by wild-type p53 [17].

Other interactions of MAP4

• We now report that, as with MAP4 and tau, MAP2 isoforms containing four (4R) instead of three (3R) tandem repeats in their microtubule binding domains do exist in human and rat brain [18].
• The association of p34cdc2/cyclin B kinase with microtubules was also shown biochemically to be mediated by MAP4 [9].
• In contrast, however, the microtubule-stabilizing activity of MAP4 was found to suppress the activities of two distinct and specific catastrophe promoters, namely, XKCM1 and a nonsequestering truncation derivative of Op18/stathmin [19].
• Cells containing mut-p53 displayed increased polymerisation of tubulin, increased protein levels of the class IV beta-tubulin isotype, STOP and survivin, and reduced protein levels of class II beta-tubulin isotype, MAP4 and FHIT [20].
• In the previous paper (Ookata et al., (1997) Biochemistry, 36: 249-259), we identified two mitotic cdc2 kinase phosphorylation sites (Ser696 and Ser787) in the proline-rich region of human MAP4 [21].

Analytical, diagnostic and therapeutic context of MAP4

• MTs polymerized by full length MAP4 were singly distributed as observed by both negative staining electron microscopy and dark field microscopy [22].
• We have reexamined the cellular distribution of MAP4, using both conventional double-label immunofluorescence and an antibody blocking technique [Schulze and Kirschner (1987) J. Cell Biol. 104:277-288] to highlight microtubules lacking, or depleted in, MAP4 [2].
• Immunohistochemistry confirmed lower MAP4 expression in tumor cells after doxorubicin treatment [3].
• Western blot analysis showed increased microtubule-associated proteins 4 (MAP4) in both cell lines [23].
• Molecular cloning techniques allowed its identification as the chicken homologue of the microtubule-associated protein 4 (MAP4), known from mammalian species, and revealed approximately 90% of its amino acid sequence [24].

References