Salam Shaaban - Academia.edu (original) (raw)

Papers by Salam Shaaban

Molecular and Cellular Biology, 1995

In order to identify catalytically important amino acid changes within the second-largest subunit... more In order to identify catalytically important amino acid changes within the second-largest subunit of yeast RNA polymerase III, we mutagenized selected regions of its gene (RET1) and devised in vivo assays for both increased and decreased transcription termination by this enzyme. Using as the reporter gene a mutant SUP4-o tRNA gene that in one case terminates prematurely and in the other case fails to terminate, we screened mutagenized RET1 libraries for reduced and increased transcription termination, respectively. The gain in suppression phenotype was in both cases scored as a reduction in the accumulation of red pigment in yeast strains harboring the ade2-1 ochre mutation. Termination-altering mutations were obtained in regions of the RET1 gene encoding amino acids 300 to 325, 455 to 486, 487 to 521, and 1061 to 1082 of the protein. In degree of amino acid sequence conservation, these range from highly variable in the first to highly conserved in the last two regions. Residues 300...

Oncotarget, Jan 12, 2015

The SMYD3 histone methyl transferase (HMTase) and the nuclear chaperone, HSP90, have been indepen... more The SMYD3 histone methyl transferase (HMTase) and the nuclear chaperone, HSP90, have been independently implicated as proto-oncogenes in several human malignancies. We show that a degenerate tetratricopeptide repeat (TPR)-like domain encoded in the SMYD3 C-terminal domain (CTD) mediates physical interaction with HSP90. We further demonstrate that the CTD of SMYD3 is essential for its basal HMTase activity and that the TPR-like structure is required for HSP90-enhanced enzyme activity. Loss of SMYD3-HSP90 interaction leads to SMYD3 mislocalization within the nucleus, thereby losing its chromatin association. This results in reduction of SMYD3-mediated cell proliferation and, potentially, impairment of SMYD3's oncogenic activity. These results suggest a novel approach for blocking HSP90-driven malignancy in SMYD3-overexpressing cells with a reduced toxicity profile over current HSP90 inhibitors.

polymerase III. second-largest subunit of yeast RNA Termination-altering mutations in the

Cancer Research, 2005

Proc Amer Assoc Cancer Res, Volume 46, 2005 4499 Lysophosphatidic acid (LPA) is a well characteri... more Proc Amer Assoc Cancer Res, Volume 46, 2005 4499 Lysophosphatidic acid (LPA) is a well characterized growth and survival factor for cancer cells in culture. This study details the identification of two G-protein coupled receptors, OSGPR78 and OSGPR114 as novel lysophosphatidic acid (LPA) receptors. OSGPR78 and OSGPR114, when expressed in a yeast-based reporter assay, are activated by multiple analogs of LPA, including myristoyl, palmitoyl, oleoyl, stearoyl and polyunsaturated LPA analogs. Similarly, when expressed in mammalian cells, the receptors also respond to the same LPA analogs. Pertussis toxin sensitivity of the effects of LPA activation of OSGPR114 expressed in CHO cells suggests a coupling to Gi/o proteins. Amino acid homologies of OSGPR114 and OSGPR78 demonstrate no obvious similarity with the known LPA G-protein coupled receptors LPA1-3. The expression of these novel LPA receptors in normal human tissues, cancer cell lines and in tumor samples has been characterized using...

Cancer Research, 2007

1025 The epithelial-mesenchymal transition (EMT) can convert epithelial tumor cells to a more met... more 1025 The epithelial-mesenchymal transition (EMT) can convert epithelial tumor cells to a more metastatic phenotype characterized by enhanced cell migration and invasion, increased resistance to anoikis and apoptosis, and greater resistance to chemotherapy or molecular targeted therapeutics. PAK1 was reported to phosphorylate Snail, a transcriptional repressor that acts as a master regulator of the epithelial-mesenchymal transition, on serine 246. Ser246 phosphorylation by PAK1 in MCF7 breast cancer cells was reported to be important for Snail translocation to the nucleus where it could repress target genes such as E-cadherin, aromatase, and occludin. Here we present supporting evidence for a positive role of both PAK1 and PAK2 kinases in a TGFβ-driven EMT model. We show that TGFβ treatment of the epithelial H358 NSCLC cell line results in downregulation of epithelial markers (E-cadherin, ErbB3) and upregulation of mesenchymal markers (N-cadherin, Snail, ZEB1). siRNA oligos targeting...

L'invention concerne un procede pour traiter un etat associe au recepteur CB-1, notamment l&#... more L'invention concerne un procede pour traiter un etat associe au recepteur CB-1, notamment l'obesite, par l'administration d'une quantite efficace d'un compose modulant un recepteur CB-1 d'uree arylique a un sujet necessitant un tel traitement.

Molecular and cellular biology, 1996

We have studied the in vitro elongation and termination properties of several yeast RNA polymeras... more We have studied the in vitro elongation and termination properties of several yeast RNA polymerase III (pol III) mutant enzymes that have altered in vivo termination behavior (S. A. Shaaban, B. M. Krupp, and B. D. Hall, Mol. Cell. Biol. 15:1467-1478, 1995). The pattern of completed-transcript release was also characterized for three of the mutant enzymes. The mutations studied occupy amino acid regions 300 to 325, 455 to 521, and 1061 to 1082 of the RET1 protein (P. James, S. Whelen, and B. D. Hall, J. Biol. Chem. 266:5616-5624, 1991), the second largest subunit of yeast RNA pol III. In general, mutant enzymes which have increased termination require a longer time to traverse a template gene than does wild-type pol III; the converse holds true for most decreased-termination mutants. One increased-termination mutant (K310T I324K) was faster and two reduced termination mutants (K512N and T455I E478K) were slower than the wild-type enzyme. In most cases, these changes in overall elonga...

Journal of Biological Chemistry, 1995

Journal of Molecular Endocrinology, Oct 1, 2001

In insects, a steroid hormone 20-hydroxyecdysone has an important role in regulating critical eve... more In insects, a steroid hormone 20-hydroxyecdysone has an important role in regulating critical events such as development and reproduction. The action of 20-hydroxyecdysone is mediated by its binding to the ecdysteroid receptor (EcR), which requires a heterodimeric partner, ultraspiracle protein (USP), a homologue of the retinoid X receptor (RXR). The EcR-USP heterodimer represents a functional receptor complex capable of initiating transcription of early genes. Our goal was to establish a ligand-dependent transactivation system in yeast utilizing an insect EcR-USP heterodimer. This has been achieved using mosquito Aedes aegypti AaEcR-USP. Expression of AaEcR alone, but not USP, resulted in constitutive transcription of the ecdysone reporter gene coupled with the Drosophila heat shock protein-27 ecdysone response elements. Removal of the N-terminal A/B domain of AaEcR abolished its constitutive transcription. Constitutive transcription was also eliminated in the presence of its heterodimeric partner, AaUSPa, AaUSPb or mammalian RXR. This suggests that the A/B domain is essential for the EcR ligand-independent transactivation and its interaction with the yeast transcription complex. A ligand-mediated transactivation of Aa(A/B)EcR-USP or Aa(A/B)EcR-RXR heterodimers in response to an ecdysteroid agonist RH-5992 was observed only in the presence of GRIP1, a mouse co-activator. In the presence of a co-repressor, SMRT, Aa(A/B)EcR-USP heterodimer exhibited a ligand-dependent repression activity. In addition, ligand-dependent transactivation systems for spruce budworm and fruit fly ecdysone receptors were also reported. This is the first report establishing the requirements of cofactors for a highly efficient ligand-dependent function of the insect EcR-USP in yeast. These findings open a way to study insect EcR-USP structure and function and to identify ligands that are specific for a certain group of insects, such as mosquitoes.

PLoS ONE, 2011

The SET and MYND Domain (SMYD) proteins comprise a unique family of multi-domain SET histone meth... more The SET and MYND Domain (SMYD) proteins comprise a unique family of multi-domain SET histone methyltransferases that are implicated in human cancer progression. Here we report an analysis of the crystal structure of the full length human SMYD3 in a complex with an analog of the S-adenosyl methionine (SAM) methyl donor cofactor. The structure revealed an overall compact architecture in which the ''split-SET'' domain adopts a canonical SET domain fold and closely assembles with a Zn-binding MYND domain and a C-terminal superhelical 9 a-helical bundle similar to that observed for the mouse SMYD1 structure. Together, these structurally interlocked domains impose a highly confined binding pocket for histone substrates, suggesting a regulated mechanism for its enzymatic activity. Our mutational and biochemical analyses confirm regulatory roles of the unique structural elements both inside and outside the core SET domain and establish a previously undetected preference for trimethylation of H4K20.