Thomas Salas | University of Pittsburgh Medical Center (original) (raw)

Papers by Thomas Salas

Research paper thumbnail of A Tat-induced auto-up-regulatory loop for superactivation of the human immunodeficiency virus type 1 promoter

Journal of virology, 1995

The virus-encoded Tat protein strongly activates transcription of human immunodeficiency virus (H... more The virus-encoded Tat protein strongly activates transcription of human immunodeficiency virus (HIV). A well-recognized mechanism involves interaction of Tat with the nascent RNA transcript of the viral tar gene; mutation of tar greatly decreases activation by Tat. However, Tat still provides a low level of activation, demonstrating that it also has a tar-independent mode of action. We propose that this tar-independent mode of Tat action is through activation of gene transcription to produce tumor necrosis factor alpha. This cytokine and other compounds that activate NF-kappa B up-regulate the HIV promoter at a low level, similarly to the second Tat action. Through this mechanism, they also activate promoters of tumor necrosis factor alpha and other cytokines and thereby establish an auto-up-regulatory loop. Activated NF-kappa B motifs in the HIV promoter synergize with Tat/tar. Mutations of these motifs decrease activation by Tat to a few percent of the wild-type value. In cooperat...

Research paper thumbnail of Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity

The Journal of biological chemistry, Jan 30, 2004

Kinases can phosphorylate and regulate androgen receptor activity during prostate cancer progress... more Kinases can phosphorylate and regulate androgen receptor activity during prostate cancer progression. In particular, we showed that glycogen synthase kinase-3 beta phosphorylates the androgen receptor, thereby inhibiting androgen receptor-driven transcription. Conversely, the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta-mediated phosphorylation of the androgen receptor, thereby enabling androgen receptor-driven transcription to occur. The androgen receptor hinge and ligand-binding domains were important for both the phosphorylation and the inhibition of transcriptional activity of the receptor by glycogen synthase kinase-3 beta. Furthermore, androgen receptor phosphorylation was augmented by LY294002, an indirect inhibitor of protein kinase B/Akt that inhibits glycogen synthase kinase-3 beta. We also showed that the mutation of various phosphorylation sites on glycogen synthase kinase-3 beta affected the ability of these m...

Research paper thumbnail of A study in the molecular and cellular functions of GSK3beta in prostate adenocarcinoma

Kinases are part of a complex network of signaling pathways that enable a cell to respond to chan... more Kinases are part of a complex network of signaling pathways that enable a cell to respond to changes in environmental conditions in a regulated and coordinated way. For example, Glycogen Synthase Kinase 3 beta (GSK3β) modulates conformational changes, protein-protein interaction, protein degradation, and activation of unique domains in proteins that transduce signals from the extracellular milieu to the nucleus. ^

Research paper thumbnail of Alleviating the Suppression of Glycogen Synthase Kinase-3  by Akt Leads to the Phosphorylation of cAMP-response Element-binding Protein and Its Transactivation in Intact Cell Nuclei

Journal of Biological Chemistry, 2003

Glycogen synthase kinase-3␤ (GSK-3␤) activity is suppressed when it becomes phosphorylated on ser... more Glycogen synthase kinase-3␤ (GSK-3␤) activity is suppressed when it becomes phosphorylated on serine 9 by protein kinase B (Akt). To determine how GSK-3␤ activity opposes Akt function we used various methods to alleviate GSK-3␤ suppression in prostate carcinoma cells. In some experiments, LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (a kinase involved in activating Akt) and tumor necrosis factor-␣ (TNF-␣) were used to activate GSK-3␤. In other experiments mutant forms of GSK-3␤, GSK-3␤ ⌬9 (a constitutively active deletion mutant of GSK-3␤) and GSK-3␤ Y216F (an inactive point mutant of GSK-3␤) were used to alter GSK-3␤ activity. LY294002, TNF-␣, and overexpression of wild-type GSK-3␤ or of GSK-3␤ ⌬9 , but not GSK-3␤ Y216F , alleviated the suppression of GSK-3␤ activity in prostate carcinoma cells and enhanced the turnover of ␤-catenin. Forced expression of wild-type GSK-3␤ or of GSK-3␤ ⌬9 , but not GSK-3␤ Y216F , suppressed cell growth and showed that the phosphorylation status of GSK-3␤ can affect its intracellular distribution. When transcription factors activator protein-1 and cyclic AMP-response element (CRE)-binding protein were analyzed as targets of GSK-3␤ activity, overexpression of wild-type GSK-3␤ suppressed AP1-mediated transcription and activated CRE-mediated transcription. Overexpression of GSK-3␤ ⌬9 caused an (80-fold) increase in CRE-mediated transcription, which was further amplified (up to 130-fold) by combining GSK-3␤ ⌬9 overexpression with the suppression of Jun activity. This study also demonstrated for the first time that expression of constitutively active GSK-3␤ ⌬9 results in the phosphorylation of CRE-binding protein on serine 129 and enhancement of CRE-mediated transcription in intact cell nuclei.

Research paper thumbnail of A Tat-induced auto-up-regulatory loop for superactivation of the human immunodeficiency virus type 1 promoter

Journal of virology, 1995

The virus-encoded Tat protein strongly activates transcription of human immunodeficiency virus (H... more The virus-encoded Tat protein strongly activates transcription of human immunodeficiency virus (HIV). A well-recognized mechanism involves interaction of Tat with the nascent RNA transcript of the viral tar gene; mutation of tar greatly decreases activation by Tat. However, Tat still provides a low level of activation, demonstrating that it also has a tar-independent mode of action. We propose that this tar-independent mode of Tat action is through activation of gene transcription to produce tumor necrosis factor alpha. This cytokine and other compounds that activate NF-kappa B up-regulate the HIV promoter at a low level, similarly to the second Tat action. Through this mechanism, they also activate promoters of tumor necrosis factor alpha and other cytokines and thereby establish an auto-up-regulatory loop. Activated NF-kappa B motifs in the HIV promoter synergize with Tat/tar. Mutations of these motifs decrease activation by Tat to a few percent of the wild-type value. In cooperat...

Research paper thumbnail of Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity

The Journal of biological chemistry, Jan 30, 2004

Kinases can phosphorylate and regulate androgen receptor activity during prostate cancer progress... more Kinases can phosphorylate and regulate androgen receptor activity during prostate cancer progression. In particular, we showed that glycogen synthase kinase-3 beta phosphorylates the androgen receptor, thereby inhibiting androgen receptor-driven transcription. Conversely, the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta-mediated phosphorylation of the androgen receptor, thereby enabling androgen receptor-driven transcription to occur. The androgen receptor hinge and ligand-binding domains were important for both the phosphorylation and the inhibition of transcriptional activity of the receptor by glycogen synthase kinase-3 beta. Furthermore, androgen receptor phosphorylation was augmented by LY294002, an indirect inhibitor of protein kinase B/Akt that inhibits glycogen synthase kinase-3 beta. We also showed that the mutation of various phosphorylation sites on glycogen synthase kinase-3 beta affected the ability of these m...

Research paper thumbnail of A study in the molecular and cellular functions of GSK3beta in prostate adenocarcinoma

Kinases are part of a complex network of signaling pathways that enable a cell to respond to chan... more Kinases are part of a complex network of signaling pathways that enable a cell to respond to changes in environmental conditions in a regulated and coordinated way. For example, Glycogen Synthase Kinase 3 beta (GSK3β) modulates conformational changes, protein-protein interaction, protein degradation, and activation of unique domains in proteins that transduce signals from the extracellular milieu to the nucleus. ^

Research paper thumbnail of Alleviating the Suppression of Glycogen Synthase Kinase-3  by Akt Leads to the Phosphorylation of cAMP-response Element-binding Protein and Its Transactivation in Intact Cell Nuclei

Journal of Biological Chemistry, 2003

Glycogen synthase kinase-3␤ (GSK-3␤) activity is suppressed when it becomes phosphorylated on ser... more Glycogen synthase kinase-3␤ (GSK-3␤) activity is suppressed when it becomes phosphorylated on serine 9 by protein kinase B (Akt). To determine how GSK-3␤ activity opposes Akt function we used various methods to alleviate GSK-3␤ suppression in prostate carcinoma cells. In some experiments, LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (a kinase involved in activating Akt) and tumor necrosis factor-␣ (TNF-␣) were used to activate GSK-3␤. In other experiments mutant forms of GSK-3␤, GSK-3␤ ⌬9 (a constitutively active deletion mutant of GSK-3␤) and GSK-3␤ Y216F (an inactive point mutant of GSK-3␤) were used to alter GSK-3␤ activity. LY294002, TNF-␣, and overexpression of wild-type GSK-3␤ or of GSK-3␤ ⌬9 , but not GSK-3␤ Y216F , alleviated the suppression of GSK-3␤ activity in prostate carcinoma cells and enhanced the turnover of ␤-catenin. Forced expression of wild-type GSK-3␤ or of GSK-3␤ ⌬9 , but not GSK-3␤ Y216F , suppressed cell growth and showed that the phosphorylation status of GSK-3␤ can affect its intracellular distribution. When transcription factors activator protein-1 and cyclic AMP-response element (CRE)-binding protein were analyzed as targets of GSK-3␤ activity, overexpression of wild-type GSK-3␤ suppressed AP1-mediated transcription and activated CRE-mediated transcription. Overexpression of GSK-3␤ ⌬9 caused an (80-fold) increase in CRE-mediated transcription, which was further amplified (up to 130-fold) by combining GSK-3␤ ⌬9 overexpression with the suppression of Jun activity. This study also demonstrated for the first time that expression of constitutively active GSK-3␤ ⌬9 results in the phosphorylation of CRE-binding protein on serine 129 and enhancement of CRE-mediated transcription in intact cell nuclei.