Inhibition of Nuclear Import by the Proapoptotic Protein CC3

King, Frank W.; Shtivelman, Emma

doi:10.1128/mcb.24.16.7091-7101.2004

Cited by 47 publications

(93 citation statements)

References 54 publications

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“…Recent results have shown that CC3 can bind directly to karyopherins of the importin ␤ family of nuclear transportins in a Ran-GTP-insensitive manner (5). For importin ␤2, the site of interaction with CC3 involves HEAT domain(s) in the Cterminal third of the protein.…”

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confidence: 99%

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Crystal Structure of CC3 (TIP30)

Omari¹,

Bird

Nichols³

et al. 2005

Journal of Biological Chemistry

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CC3 (TIP30) is a protein with pro-apoptotic and antimetastatic properties. The tumor suppressor effect of CC3 has been suggested to result from inhibition of nuclear transport by binding to importin ␤s or by regulating transcription through interaction in a complex with co-activator independent of AF-2 function (CIA) and the c-myc gene. Previous biochemical studies indicated that CC3 has protein kinase activity, and a structural similarity to cAMP-dependent protein kinase catalytic subunit was proposed. By contrast, bioinformatics studies suggested a relationship of CC3 to the short chain dehydrogenase reductase family. To clarify details of the CC3 structural family and ligand binding properties, we have determined the crystal structure of CC3 at 1.7-Å resolution. CC3 has a short chain dehydrogenase reductase fold and binding specificity for NADPH, yet it is unlikely to be normally enzymatically active because it is monomeric. These structural results, in conjunction with data from earlier mutagenesis work on the nucleotide binding motif, suggest that NADPH binding is important for the biological activity of CC3, including interaction with importins and with the CIA/c-myc system. CC3 provides an example of the adaptation of a metabolic enzyme fold to include a regulatory role, as also seen in the case of the NADH-binding co-repressor CtBP.Apoptosis or programmed cell death plays an opposing role to cell division in the homeostatic regulation of animal cell populations. As well as being of significance in development, apoptosis has an important place in the pathogenesis of some disease states. Mutated and deleted pro-apoptotic genes can give rise to carcinogenesis and tumor growth (1). CC3 (also known as TIP30) is an anti-tumor protein that predisposes cells to apoptosis, thereby giving properties of metastatic suppression (2). CC3 is an evolutionarily conserved gene ubiquitously expressed as a 27-kDa protein in human tissues. CC3 RNA is absent in variant small cell lung carcinoma cell lines that are derived from tumors with highly aggressive metastatic behavior (2). Significantly, ectopic expression of CC3 in variant small cell lung carcinoma cells induces expression of a number of apoptosis-related genes including Bad and Siva (3) and also attenuates metastasis in vivo (2). Moreover, it has been shown that genetically engineered mice deficient in CC3 have a high incidence of liver cancer and that reduced expression of CC3 is also associated with 33% of human hepatocellular carcinomas (4).A number of studies have been aimed at defining the biochemical properties of CC3, as well as the interactions made with partner proteins that may relate to its pro-apoptotic effects. Recent results have shown that CC3 can bind directly to karyopherins of the importin ␤ family of nuclear transportins in a Ran-GTP-insensitive manner (5). For importin ␤2, the site of interaction with CC3 involves HEAT domain(s) in the Cterminal third of the protein. Binding of CC3 to importins inhibits the nuclear transport of proteins with eith...

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confidence: 99%

“…Cells modified to overexpress CC3 have slower rates of nuclear transport and higher sensitivity to death signals. CC3 mutated in the region of a nucleotide binding motif (GXXGXXG, between residues 25 and 31) lacked apoptotic properties and had weakened interactions with importin ␤2 (5).…”

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Crystal Structure of CC3 (TIP30)

Omari¹,

Bird

Nichols³

et al. 2005

Journal of Biological Chemistry

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“…On the other hand, inhibition of nuclear transport factors has been reported as a powerful apoptotic trigger after a study on protein CC3. The latter impairs the function of several nuclear import receptors, such as transportin, 4 and its overexpression predisposes tumour cells to apoptosis. 5 Similarly, the reduction of importin-b and importin-a3 levels leads to an increase in the number of apoptotic cells.…”

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Inhibition of active nuclear transport is an intrinsic trigger of programmed cell death in trypanosomatids

et al. 2008

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The link between nucleocytoplasmic transport and apoptosis remains controversial. Nucleocytoplasmic exchange of molecules seems indeed essential for the initiation and execution of the apoptotic programme; but inhibition of nuclear transport factors may also represent a powerful apoptotic trigger. The GTPase Ran (together with its partners), first discovered to be essential in nucleocytoplasmic transport, has multiple key functions in cell biology, and particularly in spindle assembly, kinetochore function and nuclear envelope assembly. Among the Ran partners studied, NTF2 appears to be solely involved in nucleocytoplasmic transport. Here, we localised Ran and several of its partners, RanBP1, CAS and NTF2, at the nuclear membrane in the trypanosomatid Leishmania major. Remarkably, these proteins fused to GFP decorated a perinuclear 'collar' of about 15 dots, colocalising at nuclear pore complexes with the homologue of nucleoporin Sec13. In the other trypanosomatid Trypanosoma brucei, RNAi knockdown of the expression of the corresponding genes resulted in an apoptosis-like phenomenon. These phenotypes show that Ran and its partners have a key function in trypanosomatids like they have in mammals. Our data, notably those about TbNTF2 RNAi, support the idea that active nucleocytoplasmic transport is not essential for the initiation and execution of apoptosis, and, rather, the impairment of this transport constitutes an intrinsic signal for triggering PCD.

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“…TIP30, which exhibits decreased expression in some cancer cells NicAmhlaoibh and Shtivelman, 2001;Shtivelman, 1997;Tong et al, 2009;Zhao et al, 2006), is a tumor suppressor with proapoptotic activity (El Omari et al, 2005;Xiao et al, 2000;Zhao et al, 2007) as well as with anti-metastatic Shtivelman, 1997;Tong et al, 2009;Xiao et al, 2000;Zhao et al, 2007) and angiogenesis-inhibiting (NicAmhlaoibh and Shtivelman, 2001) properties. TIP30 binds importin-β, which facilitates the cytoplasm-to-nuclear transport of proteins (El Omari et al, 2005;King and Shtivelman, 2004;Zhao et al, 2008), including HuR (Guttinger et al, 2004;Wang et al, 2004). The cytoplasmic HuR enhances the UV irradiation-induced expression and transcriptional activity of the tumor suppressor p53 by binding to the 3′ untranslated region of its mRNA and enhancing its translation (Mazan-Mamczarz et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Second, TIP30 may act as a regulator of importin activity. It is known that TIP30 interacts with importin (El Omari et al, 2005;King and Shtivelman, 2004;Zhao et al, 2008) and importins have been shown to translocate p53 protein across the nuclear membrane by interacting with the NLS of p53 (Komlodi-Pasztor et al, 2009;Li et al, 2007). Since TIP30 protein interacts with both importin and p53, we can envision a complex in which TIP30 acts as a bridge between p53 and importin, facilitating nuclear translocation of p53.…”

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TIP30 Directly Binds p53 Tumor Suppressor Protein In Vitro

Lee

et al. 2012

Molecules and Cells

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Inhibition of Nuclear Import by the Proapoptotic Protein CC3

Cited by 47 publications

References 54 publications

Crystal Structure of CC3 (TIP30)

Crystal Structure of CC3 (TIP30)

Inhibition of active nuclear transport is an intrinsic trigger of programmed cell death in trypanosomatids

TIP30 Directly Binds p53 Tumor Suppressor Protein In Vitro

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