The Experts below are selected from a list of 207 Experts worldwide ranked by ideXlab platform
Lakshmanane Boominathan - One of the best experts on this subject based on the ideXlab platform.
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The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor Suppressor miRNAs network
Cancer and Metastasis Reviews, 2010Co-Authors: Lakshmanane BoominathanAbstract:The tumor Suppressor p53 homologues, TA-p73, and p63 have been shown to function as tumor Suppressors. However, how they function as tumor Suppressors remains elusive. Here, I propose a number of tumor Suppressor pathways that illustrate how the TA-p73 and p63 could function as negative regulators of invasion, metastasis, and cancer stem cells (CSCs) proliferation. Furthermore, I provide molecular insights into how TA-p73 and p63 could function as tumor Suppressors. Remarkably, the guardians—p53, p73, and p63—of the genome are in control of most of the known tumor Suppressor miRNAs, tumor Suppressor genes, and metastasis Suppressors by suppressing c-myc through miR-145/let-7/miR-34/TRIM32/PTEN/FBXW7. In particular, p53 and TA-p73/p63 appear to upregulate the expression of (1) tumor Suppressor miRNAs, such as let-7, miR-34, miR-15/16a, miR-145, miR-29, miR-26, miR-30, and miR-146a; (2) tumor Suppressor genes, such as PTEN, RBs, CDKN1a/b/c, and CDKN2a/b/c/d; (3) metastasis Suppressors, such as Raf kinase inhibitory protein, CycG2, and DEC2, and thereby they enlarge their tumor Suppressor network to inhibit tumorigenesis, invasion, angiogenesis, migration, metastasis, and CSCs proliferation.
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∆N-p63 functions as an invasion, migration, and metastasis Suppressor
Nature Precedings, 2010Co-Authors: Lakshmanane BoominathanAbstract:The tumor Suppressor p53 homologues, TA-p73, and p63 have been shown to function as tumor Suppressors. However, how they function as tumor Suppressors remains elusive. Expression of p63 is controlled by two distinct promoters. Consequently, this results in two different gene products such as TA-(transactivation domain containing NH2 terminus) p63 and ∆N-(lacks NH2 terminus) p63. It is generally thought that the TA-p63 functions as a tumor Suppressor, while the ∆N-p73 functions as a proto-oncogene. However, careful interpretation of the data concerning ∆N-p63 suggests that it could function as an invasion and metastasis/tumor Suppressor in a cell context dependent manner.
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The guardians of the genome dependent tumor Suppressor miRNAs network
Nature Precedings, 2009Co-Authors: Lakshmanane BoominathanAbstract:The tumor Suppressor p53 homologues, TA-p73, and p63 have been shown to function as tumor Suppressors. However, how they function as tumor Suppressors remains elusive. Here I present a number of models that illustrates how the TA-p73/p63 could function as tumor Suppressors. Remarkably, the guardians—p53, p63, and p73—of the genome are in control of most of the known tumor Suppressor miRNAs. TA-p73/p63 and p53, by suppressing the expression of c-Myc through TRIM32 and miR-145, they could up regulate the expression of tumor Suppressor microRNAs, such as miR-15/16a, miR-29, miR-34, miR-26, let-7a/d/g, miR-30b/c/d/e, miR-146a, and a number of tumor Suppressor genes. It appears that p53/TA-p73/p63-mediated repression of c-myc (and its repressed miRNA targets) inhibits tumor growth. Thus, these findings strongly suggest that p53, TA-p73 and TA-p63, by suppressing the expression of c-myc, they could increase c-myc-repressed tumor Suppressor miRNAs, and thereby they could function as tumor Suppressors. In addition, TA-p73/p63 and p53 appears to regulate the expression of miR-200b, c to control EMT, invasion and metastasis.Remarkably, microRNA processing components, such as dicer, P2P-R, Ago1/2, DGCR-8, are regulated by p53, p73, and p63. By regulating the miRNA processing components, they could function as regulators of miRNA/siRNA biogenesis. Therefore, these studies suggest that the guardians of the genome p53, p73 and p63 are in control of the biogenesis of miRNAs as well. Taken together, “the guardians of the genome integrity,” p53, TA-p73 and TA-p63 are not only in control of its protein coding targets, but also non-coding tumor Suppressor microRNAs and thereby they enlarge their tumor Suppressor network to inhibit tumorigenesis.
Jonathan King - One of the best experts on this subject based on the ideXlab platform.
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identification of global Suppressors for temperature sensitive folding mutations of the p22 tailspike protein
Journal of Biological Chemistry, 1991Co-Authors: Bentley A Fane, Robert Villafane, Anna Mitraki, Jonathan KingAbstract:Abstract Suppressor mutations which alleviate the defects in folding mutants of the P22 gene 9 tailspike protein have recently been isolated (Fane, B. and King, J. (1991) Genetics 127, 263-277). The starting folding defects were in missense polypeptide chains generated by host amino acid insertions at different amber mutant sites. Fragments of genes carrying the amber mutations with and without their independently isolated Suppressor mutations were cloned and sequenced. The parental nonsense mutations were located at Q45, K122, E156, W202, W207, Y232, and W365. Their conformational Suppressors were single amino acid substitutions at a limited set of sites, V84 greater than A, V331 greater than A, and A334 greater than V. The V331 greater than A or A334 greater than V Suppressors were independently recovered starting with different mutant sites suggesting that they acted by some global or general mechanism. When the V331 greater than A and A334 greater than V mutations were crossed into well-characterized temperature-sensitive folding (tsf) mutants at various sites in the tailspike protein, they suppressed all of the eight tsf mutants tested. Since the tsf defects destabilize folding intermediates rather than the native conformation, this result implies that the Suppressors act in the folding pathway. Strains carrying the isolated Suppressor mutations displayed no obvious phenotypic defect and formed native biologically active tailspikes. Thus, these single amino acid substitutions have striking influences on the efficiency of intracellular chain folding, without causing functional defects in the native protein.
Rasmus Hartmannpetersen - One of the best experts on this subject based on the ideXlab platform.
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single site Suppressors of a fission yeast temperature sensitive mutant in cdc48 identified by whole genome sequencing
PLOS ONE, 2015Co-Authors: Irina N Marinova, Jacob Engelbrecht, Adrian Ewald, Lasse Langholm, Christian Holmberg, Birthe B Kragelund, Colin Gordon, Olaf Nielsen, Rasmus HartmannpetersenAbstract:The protein called p97 in mammals and Cdc48 in budding and fission yeast is a homo-hexameric, ring-shaped, ubiquitin-dependent ATPase complex involved in a range of cellular functions, including protein degradation, vesicle fusion, DNA repair, and cell division. The cdc48+ gene is essential for viability in fission yeast, and point mutations in the human orthologue have been linked to disease. To analyze the function of p97/Cdc48 further, we performed a screen for cold-sensitive Suppressors of the temperature-sensitive cdc48-353 fission yeast strain. In total, 29 independent pseudo revertants that had lost the temperature-sensitive growth defect of the cdc48-353 strain were isolated. Of these, 28 had instead acquired a cold-sensitive phenotype. Since the Suppressors were all spontaneous mutants, and not the result of mutagenesis induced by chemicals or UV irradiation, we reasoned that the genome sequences of the 29 independent cdc48-353 Suppressors were most likely identical with the exception of the acquired Suppressor mutations. This prompted us to test if a whole genome sequencing approach would allow us to map the mutations. Indeed genome sequencing unambiguously revealed that the cold-sensitive Suppressors were all second site intragenic cdc48 mutants. Projecting these onto the Cdc48 structure revealed that while the original temperature-sensitive G338D mutation is positioned near the central pore in the hexameric ring, the Suppressor mutations locate to subunit-subunit and inter-domain boundaries. This suggests that Cdc48-353 is structurally compromized at the restrictive temperature, but re-established in the Suppressor mutants. The last Suppressor was an extragenic frame shift mutation in the ufd1 gene, which encodes a known Cdc48 co-factor. In conclusion, we show, using a novel whole genome sequencing approach, that Cdc48-353 is structurally compromized at the restrictive temperature, but stabilized in the Suppressors.
Dennis M. Livingston - One of the best experts on this subject based on the ideXlab platform.
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Allele-specific suppression of temperature-sensitive mutations of theSaccharomyces cerevisiae RAD52 gene
Current Genetics, 1996Co-Authors: Michael D. Kaytor, Dennis M. LivingstonAbstract:We screened for rad52 Suppressors against temperature-sensitive (ts), missense, nonsense, and deletion rad52 mutations. Except for the deletion strain all mutants yielded Suppressor candidates, indicating that Suppressors completely bypassing the need for RAD52 are rare. Characterization of seven, recessive extragenic Suppressors from our screen and two previously identified Suppressors revealed that nearly all exhibit allele specificity. The allele specificity is positional in that Suppressors that suppress a is mutation in the C-terminal third of the coding region do not suppress three is mutations in the N-terminal third. Conversly, Suppressors against one of the three N-terminal mutations suppress more than one of these mutations but not the C-terminal mutation.
Carolyn M Teschke - One of the best experts on this subject based on the ideXlab platform.
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single amino acid substitutions globally suppress the folding defects of temperature sensitive folding mutants of phage p22 coat protein
Journal of Biological Chemistry, 1999Co-Authors: Lili A Aramli, Carolyn M TeschkeAbstract:Abstract The amino acid sequence of a polypeptide defines both the folding pathway and the final three-dimensional structure of a protein. Eighteen amino acid substitutions have been identified in bacteriophage P22 coat protein that are defective in folding and cause their folding intermediates to be substrates for GroEL and GroES. These temperature-sensitive folding (tsf) substitutions identify amino acids that are critical for directing the folding of coat protein. Additional amino acid residues that are critical to the folding process of P22 coat protein were identified by isolating second site Suppressors of the tsf coat proteins. Suppressor substitutions isolated from the phage carrying the tsf coat protein substitutions included global Suppressors, which are substitutions capable of alleviating the folding defects of numerous tsf coat protein mutants. In addition, potential global and site-specific Suppressors were isolated, as well as a group of same site amino acid substitutions that had a less severe phenotype than the tsf parent. The global Suppressors were located at positions 163, 166, and 170 in the coat protein sequence and were 8–190 amino acid residues away from the tsf parent. Although the folding of coat proteins with tsf amino acid substitutions was improved by the global Suppressor substitutions, GroEL remained necessary for folding. Therefore, we believe that the global Suppressor sites identify a region that is critical to the folding of coat protein.
