A novel zinc finger coiled-coil domain in a family of nuclear proteins

Reddy, Bramham A.; Etkin, Laurence D.; Freemont, Paul S.

doi:10.1016/0968-0004(92)90308-v

Cited by 252 publications

(155 citation statements)

References 12 publications

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“…All these motifs are reported to be involved in protein ± protein interactions. The B-box domains of Brat are of type 1 and 2, respectively (Reddy et al, 1992). Both are made of 34 amino acids, and are separated by 115 amino acids.…”

Section: The Brat Proteinmentioning

confidence: 99%

“…The Brat coiled-coil domain is 136 amino acids long (Lupas, 1996). It is located immediately after the B box domains, similarly to several other B boxcontaining proteins (Reddy et al, 1992). The C-terminus region of Brat consists of a b-propeller domain made of six NHL repeats (®rst identi®ed in three proteins, Ncl-1, HT2A and LIN-41; Slack and Ruvkun, 1998).…”

Section: The Brat Proteinmentioning

confidence: 99%

“…The B-box motifs, which have been found in several oncoproteins such as PML, RET, and T18 (Reddy et al, 1992), were shown to bind one zinc atom and are likely to represent sites of protein ± protein interactions . Proteins of the Ring ®nger/B-box/Coiled-Coil (RBCC) group contain highly conserved zinc-binding RING ®nger and one or two zinc-binding B-box domains, followed by a coiled-coil domain (Reddy et al, 1992;Saurin et al, 1996). Brat represents a new subgroup of the Bbox proteins that contains only two B-box domains followed by a coiled-coil domain without the RING ®nger.…”

Section: Three Protein-binding Motifs In the Brat Proteinmentioning

confidence: 99%

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Mutations in the β-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain

et al. 2000

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Inactivation of both alleles of the fruit¯y D. melanogaster brain tumor (brat) gene results in the production of a tumor-like neoplasm in the larval brain, and lethality in the larval third instar and pupal stages. We cloned the brat gene from a transposon-tagged allele and identi®ed its gene product. brat encodes for an 1037 amino acid protein with an N-terminal B-box1 zinc ®nger followed by a B-box2 zinc ®nger, a coiled-coil domain, and a C-terminal b-propeller domain with six blades. All these motifs are known to mediate protein ± protein interactions. Sequence analysis of four brat alleles revealed that all of them are mutated at the bpropeller domain. The clustering of mutations in this domain strongly suggests that it has a crucial role in the normal function of Brat, and de®nes a novel protein motif involved in tumor suppression activity. The brat gene is expressed in the embryonic central and peripheral nervous systems including the embryonic brain. In third instar larva brat expression was detected in the larval central nervous system including the brain and the ventral ganglion, in two glands ± the ring gland and the salivary gland, and in parts of the foregut ± the gastric caecae and the proventriculus. A second brat-like gene was found in D. melanogaster, and homologs were identi®ed in the nematode, mouse, rat, and human. Accumulated data suggests that Brat may regulate proliferation and di erentiation by secretion/transportmediated processes.

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Section: The Brat Proteinmentioning

confidence: 99%

Section: The Brat Proteinmentioning

confidence: 99%

Section: Three Protein-binding Motifs In the Brat Proteinmentioning

confidence: 99%

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Mutations in the β-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain

et al. 2000

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“…PML belongs to a family of proteins which share an aminoterminal tripartite domain characterized by the C 3 HC 4 zinc ®nger motif, named Ring ®nger, one or two additional cysteine-rich regions (B-boxes) and a coiled-coil region Lovering et al, 1993;Reddy et al, 1992). Many members of this family are transcriptional regulators, some display DNA binding function and two (RFP, T18/TIF1) are, like PML, involved in genetic recombinations that lead to the formation of transforming fusion proteins (RFP/ret and T18/B-raf, respectively) (Gandini and Pandol®, 1994;Le Douarin et al, 1995;Tkahashi et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Cooperation between the RING+B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival

et al. 1998

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PML/RARa is the abnormal protein product of the Acute Promyelocytic Leukemia-speci®c 15;17 translocation. Both the PML and RARa components are required for the PML/RARa biological activities, namely its capacity to block di erentiation and to increase survival of haematopoietic precursors. The physiological role of PML and its contribution to the function of the fusion protein are unknown. PML localizes to the cytoplasm and within speci®c nuclear bodies (NBs). In vitro, overexpression of PML correlates with suppression of cell transformation. The PML aminoterminal portion retained within the PML/RARa protein contains the RING ®nger, two newly de®ned cystein/histidine-rich motifs called Bboxes (B1 and B2) and a coiled-coil region. We report here that PML has a growth suppressive activity in all the cell lines tested, regardless of their transformed phenotype, and that the cellular basis for the PML growth suppression is induction of apoptotic cell death. Analysis of various nuclear and cytoplasmic PML isoforms showed that the PML growth suppressive activity correlates with its nuclear localization. Analysis of the localization and growth suppressive activity demonstrated that: (i) the Ring+B1-B2 and coiled-coil regions are both indispensable and su cient to target PML to the NBs; (ii) individual deletions of the various PML domains have no e ect on its growth suppressor activity; (iii) the Ring+B1-B2 region exerts a partial growth suppressor activity but its fusion with the coiled-coil region is su cient to recapitulate the suppressive function of wild type PML. These results indicate that PML is involved in cell survival regulation and that the PML component of the fusion protein (Ring+B1-B2 and coiled-coil regions) retains intact biological activity, thereby suggesting that the e ects of PML/RARa on survival derive from the activation of the incorporated PML sequence.

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“…The presence of the RING-®nger and B-box motifs classi®es PML into a large family of proteins that include transcription regulatory factors and proteins involved in oncogenesis (Freemont et al, 1991;Reddy et al, 1992). Recent investigations have provided evidence supporting the involvement of PML in the regulation (repression and activation) of transcription.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Fos-mediated AP-1 transcription by the promyelocytic leukemia protein

et al. 1998

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The growth and transformation suppressor function of promyelocytic leukemia (PML) protein are disrupted in acute promyelocytic leukemia (APL) as a result of its fusion to the RARa gene by t(15;17) translocation. There is signi®cant sequence homology between the dimerization domain of PML and the Fos family of proteins, which imply that PML may be involved in AP-1 activity. Here we show that PML can cooperate with Fos to stimulate its AP-1-mediated transcriptional activity. Cotransfection of PML with GAL4/Fos strongly induced Fos-mediated activation of GAL4-responsive reporters, indicating a functional interaction between Fos and PML in vivo. Deletion analysis of Fos and PML demonstrated that the intact C-terminal domain of Fos (containing the dimerization domain), and the RING-®nger, B1 box and nuclear localization domains of PML are involved in the cooperative activity of Fos and PML. Immunoprecipitation and electrophoretic mobility shift assay showed that PML is associated with the AP-1 complex. PMLRARa was also found to enhance the transcriptional activity of GAL4/Fos. The addition of retinoic acid abrogated the PMLRARa, but not PML-induced stimulation of GAL4/Fos activity in a dose-dependent manner. This study demonstrated that PML is involved in the AP-1 complex and can modulate Fos-mediated transcriptional activity, which may contribute to its growth suppressor function.

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A novel zinc finger coiled-coil domain in a family of nuclear proteins

Cited by 252 publications

References 12 publications

Mutations in the β-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain

Mutations in the β-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain

Cooperation between the RING+B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival

Modulation of Fos-mediated AP-1 transcription by the promyelocytic leukemia protein

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