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A long-range foresight for the medical application of apoptosis specifically induced by Dd-MRP4, Dictyostelium mitochondrial ribosomal protein S4, to cancer therapy.

Maeda Y - Biomolecules (2015)

Bottom Line: Apoptosis (programmed cell death) is regarded as ultimate differentiation of the cell.This amazing fact was discovered, simply based on the finding that Dd-MRP4 expression is absolutely required for transition of Dictyostelium cells from growth to differentiation (Chida et al., 2008, doi:10.1186/1471-2156-9-25; Maeda et al., 2013, doi:10.3390/biom3040943).Dd-MRP4 protein has quite unique structural characters, in that it is highly basic (pI: about 11.5) and interestingly has several nuclear-localization signals within the molecule.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan. kjygy352@ybb.ne.jp.

ABSTRACT
Apoptosis (programmed cell death) is regarded as ultimate differentiation of the cell. We have recently demonstrated that a targeted delivery of Dd-MRP4 (Dictyostelium mitochondrial ribosomal protein S4) suppresses specifically the proliferation of the human cancer cells, by inducing their apoptotic cell death (Chida et al., 2014, doi:10.1186/1475-2867-14-56). This amazing fact was discovered, simply based on the finding that Dd-MRP4 expression is absolutely required for transition of Dictyostelium cells from growth to differentiation (Chida et al., 2008, doi:10.1186/1471-2156-9-25; Maeda et al., 2013, doi:10.3390/biom3040943). Dd-MRP4 protein has quite unique structural characters, in that it is highly basic (pI: about 11.5) and interestingly has several nuclear-localization signals within the molecule. In this review, we introduce briefly the efficacy of several apoptosis-inducing substances reported thus far for cancer therapy, and speculate the possible mechanisms, by which apoptosis is specifically induced by Dd-MRP4, on the basis of its structural uniqueness. We also discuss several issues to be solved for the medical application of ectopically expressed Dd-MRP4 in human cancer cells.

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Related in: MedlinePlus

Unique structure of Dd-MRP4 molecule. Based on the presence of S4 RNA binding domain (yellow box), this molecule is categorized into ribosomal protein S4, though its amino acid sequence is markedly different from Dictyostelium cytoplasmic ribosomal protein S4 (Dd-RPS4) as a whole. Dd-MRP4 is highly basic (pI: about 11.5) because of the quite high contents of lysine (K) and arginine (R), and interestingly has several nuclear localization signals (underlined regions) within the molecule.
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biomolecules-05-00113-f001: Unique structure of Dd-MRP4 molecule. Based on the presence of S4 RNA binding domain (yellow box), this molecule is categorized into ribosomal protein S4, though its amino acid sequence is markedly different from Dictyostelium cytoplasmic ribosomal protein S4 (Dd-RPS4) as a whole. Dd-MRP4 is highly basic (pI: about 11.5) because of the quite high contents of lysine (K) and arginine (R), and interestingly has several nuclear localization signals (underlined regions) within the molecule.

Mentions: Although Dictyostelium is evolutionally far from human, the homology of Dictysteiulm cytoplasmic ribosomal protein S4 (Dd-RPS4: 267 amino acids) and human choromosome X-linked cytoplasmic ribosomal protein S4 (Hs-RPS4X; 263 amino acids) is considerably high (66% identity, 92% similarity in the amino acid sequence). In contrast, Dd-MRP4 differs widely from Dd-RPS4 and Hs-RPS4X. Here it is of interest to note that Dd-MRP4 differs considerably from Dd-RPS4 in structure and function, and surprisingly that it has several nuclear localization signals within the molecule (Figure 1; underlined parts). Actually, Dd-MRP4 overexpressed in the cytoplasm of Dictyostelium cells has been confirmed to be preferentially transferred to the nucleus [24]. The reason why Dd-MRP4 can be encoded by mitochondrial genome itself in the cytoplasm of Dictyostelium cells is mysterious and remains to be elucidated as a chain of evolutionally amazing and rather unexpected incident, because MRPs are generally encoded by nuclear genome in eukaryotic cells. Dd-MRP4 is highly basic (pI: about 11.5), just like histone, and easily imagined to bind readily with DNA and/or RNA. Homology of Dd-MRP4 to Dd-RPS4 (cytoplasmic Dictyostelium ribosomal protein) and HRPS4 (human ribosomal protein) is quite low, as previously described [4], though it has a S4 RNA binding domain that probably mediates binding to RNA.


A long-range foresight for the medical application of apoptosis specifically induced by Dd-MRP4, Dictyostelium mitochondrial ribosomal protein S4, to cancer therapy.

Maeda Y - Biomolecules (2015)

Unique structure of Dd-MRP4 molecule. Based on the presence of S4 RNA binding domain (yellow box), this molecule is categorized into ribosomal protein S4, though its amino acid sequence is markedly different from Dictyostelium cytoplasmic ribosomal protein S4 (Dd-RPS4) as a whole. Dd-MRP4 is highly basic (pI: about 11.5) because of the quite high contents of lysine (K) and arginine (R), and interestingly has several nuclear localization signals (underlined regions) within the molecule.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384114&req=5

biomolecules-05-00113-f001: Unique structure of Dd-MRP4 molecule. Based on the presence of S4 RNA binding domain (yellow box), this molecule is categorized into ribosomal protein S4, though its amino acid sequence is markedly different from Dictyostelium cytoplasmic ribosomal protein S4 (Dd-RPS4) as a whole. Dd-MRP4 is highly basic (pI: about 11.5) because of the quite high contents of lysine (K) and arginine (R), and interestingly has several nuclear localization signals (underlined regions) within the molecule.
Mentions: Although Dictyostelium is evolutionally far from human, the homology of Dictysteiulm cytoplasmic ribosomal protein S4 (Dd-RPS4: 267 amino acids) and human choromosome X-linked cytoplasmic ribosomal protein S4 (Hs-RPS4X; 263 amino acids) is considerably high (66% identity, 92% similarity in the amino acid sequence). In contrast, Dd-MRP4 differs widely from Dd-RPS4 and Hs-RPS4X. Here it is of interest to note that Dd-MRP4 differs considerably from Dd-RPS4 in structure and function, and surprisingly that it has several nuclear localization signals within the molecule (Figure 1; underlined parts). Actually, Dd-MRP4 overexpressed in the cytoplasm of Dictyostelium cells has been confirmed to be preferentially transferred to the nucleus [24]. The reason why Dd-MRP4 can be encoded by mitochondrial genome itself in the cytoplasm of Dictyostelium cells is mysterious and remains to be elucidated as a chain of evolutionally amazing and rather unexpected incident, because MRPs are generally encoded by nuclear genome in eukaryotic cells. Dd-MRP4 is highly basic (pI: about 11.5), just like histone, and easily imagined to bind readily with DNA and/or RNA. Homology of Dd-MRP4 to Dd-RPS4 (cytoplasmic Dictyostelium ribosomal protein) and HRPS4 (human ribosomal protein) is quite low, as previously described [4], though it has a S4 RNA binding domain that probably mediates binding to RNA.

Bottom Line: Apoptosis (programmed cell death) is regarded as ultimate differentiation of the cell.This amazing fact was discovered, simply based on the finding that Dd-MRP4 expression is absolutely required for transition of Dictyostelium cells from growth to differentiation (Chida et al., 2008, doi:10.1186/1471-2156-9-25; Maeda et al., 2013, doi:10.3390/biom3040943).Dd-MRP4 protein has quite unique structural characters, in that it is highly basic (pI: about 11.5) and interestingly has several nuclear-localization signals within the molecule.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan. kjygy352@ybb.ne.jp.

ABSTRACT
Apoptosis (programmed cell death) is regarded as ultimate differentiation of the cell. We have recently demonstrated that a targeted delivery of Dd-MRP4 (Dictyostelium mitochondrial ribosomal protein S4) suppresses specifically the proliferation of the human cancer cells, by inducing their apoptotic cell death (Chida et al., 2014, doi:10.1186/1475-2867-14-56). This amazing fact was discovered, simply based on the finding that Dd-MRP4 expression is absolutely required for transition of Dictyostelium cells from growth to differentiation (Chida et al., 2008, doi:10.1186/1471-2156-9-25; Maeda et al., 2013, doi:10.3390/biom3040943). Dd-MRP4 protein has quite unique structural characters, in that it is highly basic (pI: about 11.5) and interestingly has several nuclear-localization signals within the molecule. In this review, we introduce briefly the efficacy of several apoptosis-inducing substances reported thus far for cancer therapy, and speculate the possible mechanisms, by which apoptosis is specifically induced by Dd-MRP4, on the basis of its structural uniqueness. We also discuss several issues to be solved for the medical application of ectopically expressed Dd-MRP4 in human cancer cells.

Show MeSH
Related in: MedlinePlus