Larry Hightower | University of Connecticut-storrs (original) (raw)

Conference Presentations by Larry Hightower

Session topics include: Comparative Biology of Stress Proteins and Longevity Compartment-specific... more Session topics include:
Comparative Biology of Stress Proteins and Longevity
Compartment-specific and Extracellular HSPs and Other Molecular Chaperones
Global Regulatory Networks of Stress Genes
Molecular Chaperones in Development and Growth
Molecular Chaperones and Proteostasis
New Drugs and Therapeutic Interventions in Stress and Aging Related Disease
Oxidative/Reductive Stress Responses
Quality Control Mechanisms
Stress Immunity and Metabolism
Stress Management in Human Disease
Stress Responses and the Environment
Stress Responses in Women's Health

Papers by Larry Hightower

Cell Stress & Chaperones, Jul 15, 2008

Cell Stress & Chaperones, 2019

The stress response has been studied now for over 50 years and is known to have significance in t... more The stress response has been studied now for over 50 years and is known to have significance in the survival of organisms in a challenging environment and in the healthy development of all known descendants of the last common universal ancestor (LUCA). This meeting was concentrated mostly on the responses of cells and organisms to environmental and cell stress including the impact of thermal stress, which was a major theme throughout this meeting. One emphasis was on the deployment of the heat shock response that permits damage to proteins to be detected and responded to by the abundant synthesis of heat shock proteins (HSPs). Speakers and presenters of posters responded to the questions of how are the HSPs rapidly induced by stressors? By which mechanisms are they are regulated in the cell by protein-protein interactions or posttranslational modification? And, what are the consequences when these abundantly expressed proteins escape the confines of the cell and influence the extracellular microenvironment? Key among the questions was how does stress influence longevity and aging and what happens in terms of disease control (malignant, neurodegenerative) when stress responses become compromised? In this context, many presenters addressed the question of pharmacologically modifying the heat shock response and HSP functions and thus improving responses to a range of disease types.

Cell Stress & Chaperones, 2007

Heat shock protein (Hsp) 70BЈ is a human Hsp70 chaperone that is strictly inducible, having littl... more Heat shock protein (Hsp) 70BЈ is a human Hsp70 chaperone that is strictly inducible, having little or no basal expression levels in most cells. Using siRNAs to knockdown Hsp70BЈ and Hsp72 in HT-29, SW-480, and CRL-1807 human colon cell lines, we have found that the two are regulated coordinately in response to stress. We also have found that proteasome inhibition is a potent activator of Hsp70BЈ. Flow cytometry was used to assay Hsp70BЈ promoter activity in HT-29eGFP cells in this study. Knockdown of both Hsp70BЈ-and Hsp72-sensitized cells to heat stress and increasing concentrations of proteasome inhibitor. These data support the conclusion that Hsp72 is the primary Hsp70 family responder to increasing levels of proteotoxic stress, and Hsp70BЈ is a secondary responder. Interestingly ZnSO 4 induces Hsp70BЈ and not Hsp72 in CRL-1807 cells, suggesting a stressor-specific primary role for Hsp70BЈ. Both Hsp70BЈ and Hsp72 are important for maintaining viability under conditions that increase the accumulation of damaged proteins in HT-29 cells. These findings are likely to be important in pathological conditions in which Hsp70BЈ contributes to cell survival.

Molecular Biology and Evolution, 1995

Journal of Virology, 1975

We have studied the relationships among the polypeptides of Newcastle disease virus by using both... more We have studied the relationships among the polypeptides of Newcastle disease virus by using both kinetic and tryptic peptide analyses. The results of our tryptic peptide analyses suggest that there are at least six unique viral polypeptides--L, HN, FO(F), NP, M, and a 47,000-dalton polypeptide. The small virion glycopolypeptide F is related to FO, a glycopolypeptide found only in infected cells. In addition, several smaller polypeptides, including a 53,000-dalton polypeptide found both in purified virions and in infected cells, are related to the nucleocaspid protein. Kinetic analysis of each viral polypeptide reveals that all of the major viral polypeptides, with the possible exception of L, are stable after an amino acid chase. A precursor-product relationship between FO and F was not demonstrable by pulse-chase experiments. Also, almost the same relative amount of F, the putative product, was present in infected cultures after either 5 or 30 min of radioisotopic labeling. These ...

Marine Environmental Research, 1993

Cell Stress and Chaperones, 2019

Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archa... more Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archaea, bacteria, and eukaryota. sHSPs belong to the superfamily of molecular chaperones: they are components of the cellular protein quality control machinery and are thought to act as the first line of defense against conditions that endanger the cellular proteome. In plants, sHSPs protect cells against abiotic stresses, providing innovative targets for sustainable agricultural production. In humans, sHSPs (also known as HSPBs) are associated with the development of several neurological diseases. Thus, manipulation of sHSP expression may represent an attractive therapeutic strategy for disease treatment. Experimental evidence demonstrates that enhancing the chaperone function of sHSPs protects against age-related protein conformation diseases, which are characterized by protein aggregation. Moreover, sHSPs can promote longevity and healthy aging in vivo. In addition, sHSPs have been implicated in the prognosis of several types of cancer. Here, sHSP upregulation, by enhancing cellular health, could promote cancer development; on the other hand, their downregulation, by sensitizing cells to external stressors and chemotherapeutics, may have beneficial outcomes. The complexity and diversity of sHSP function and properties and the need to identify their specific clients, as well as their implication in human disease, have been discussed by many of the world's experts in the sHSP field during a dedicated workshop in Québec City, Canada, on 26-29 August 2018.

Proceedings of the …, 1992

Cell Stress & Chaperones, 2021

I retired as Editor-in-Chief on December 31, 2020, after 25 years. Cell Stress & Chaperones was m... more I retired as Editor-in-Chief on December 31, 2020, after 25 years. Cell Stress & Chaperones was my cultural baby and I watched it grow as an infant and develop into a child and young adult. But like biological children, journals are unlikely to mature into independent, fully functional adults if the parents hold their child closely for too long. One reason that I can retire comfortably at this moment is that our journal has a very talented board of Senior Editors that includes Bill Currie. Another reason is that our founding Office Manager Helen Neumann, bringing her wealth of knowledge gained from 25 years of experience, is continuing with the Journal. Bill introduced himself to me at the 1985 Cold Spring Harbor Heat Shock Meeting. I think he was surprised that I knew much of his post-doctoral work with his mentor Fredric P. White. Fred and I had met about 7 years earlier following a string of events sufficiently unique and improbable as to raise the possibility of Divine guidance....

Cell Stress and Chaperones

Cell Stress and Chaperones, 2016

The Seventh International Congress of the Cell Stress Society International (CSSI) was held as a ... more The Seventh International Congress of the Cell Stress Society International (CSSI) was held as a joint meeting with the newly organized committee of Stress Physiology, the Chinese Association for Physiological Sciences (CAPS). There were over 200 colleagues and their students in attendance from 22 different countries. The topics of the congress were core scientific areas in the field of stress and health. The keynote speakers were Fu-Chu He (China), E.R. (Ron) de Kloet (The Netherlands), and Kazuhiro Nagata (Japan). The CSSI Medallion for Career Achievement in the cell stress and chaperones field was awarded to Kazutoshi Mori (Japan). Twelve student post awards were given in recognition of a very high quality poster session. In the tradition of this series of congresses, cultural events were an important part of the program. In addition, participants became better acquainted during trips to the ancient shopping street, an evening at the Chinese opera, and a lesson in Tai Chi from a master. The first groups of CSSI Fellows and Senior Fellows were presented their rosettes and certificates during the congress.

Results and Problems in Cell Differentiation, 1991

ABSTRACT

Heat Shock Proteins, 2015

HSP27 is essential for mammalian cell movement. To further explore the effects of heat shock and ... more HSP27 is essential for mammalian cell movement. To further explore the effects of heat shock and the mechanistic role of HSP27, we have initiated a study using a well-established model of rapidly moving cells, the fi sh keratocyte. Here we report that heat shock causes a decrease in cell speed. Since changes in cell morphology can drastically affect cell movement, we also monitored changes in cell morphology. Heat shock caused a decrease in the number of polar cells and an increase in those with one stuck adherent edge, indicating the occurrence of both cytoskeletal reorganization and increased adhesion to substrata. Analyses of HSP27 levels using Western blots showed they were relatively high in keratocytes prior to heat shock and remained high afterward. In contrast, Western blot analysis of HSP70 showed that it was induced strongly by heat shock, indicating that fi sh keratocytes mounted a robust heat shock response. Surprisingly, given the propensity of HSP27 to localize in nuclear/perinuclear regions following heat shock, the location of HSP27 in fi sh keratocytes was unchanged as shown by indirect immunostaining with anti-HSP27 antibodies. Fluorescence intensities of immunostained images of cells before and after heat shock were quantifi ed using Image J software. The results of this analysis showed that fl uorescence intensity decreased following heat shock, suggesting changes in HSP27 that affected antibody recognition. Possible roles for HSP27 in regulating actin fi lament dynamics, cell speed and morphology are discussed.

Biocompatible matrices, such as bovine collagen, have demonstrated usefulness in delivering gene ... more Biocompatible matrices, such as bovine collagen, have demonstrated usefulness in delivering gene therapy vectors that express growth factors to local environments for tissue repair. Unlike animal derived matrices, we have developed a new synthetic matrix consisting of a linear cyclodextrin-polyethyleneglycol co-polymer that is non-covalently cross-linked with di-adamantane-polyethyleneglycol via inclusion complex formation between adamantane and cyclodextrin (CD-Ada). We performed both in vitro and in vivo experiments for biocompatibility and localized transgene expression using a recombinant adenovirus (rAd) vector containing either the reporter gene, GFP, or the therapeutic gene, PDGF-B. In vitro results demonstrated cell migration, adenoviral transduction, and gene expression with no visible signs of toxicity in human skin fibroblasts. Qualitative gene expression from the CD-Ada containing rAd was delayed by approximately two days when compared to collagen, but the level of expression was greater over a longer period of time. In vivo experiments demonstrated gene expression after local delivery to mouse skin using rAd-GFP in CD-Ada. Again, the expression was slightly delayed but duration of expression was comparable to collagen. Expression studies using rAd-PDGF-B, were performed in the rat polyvinyl alcohol sponge model and showed comparable quantitative DNA and RNA levels between CD-Ada and collagen (DNA: 4.1 • 10 10 and 4.5 • 10 10 MEQ of PDGF-B/assayed sponge, respectively; RNA: 7.0 • 10 8 and 3.2 • 10 8 MEQ of PDGF-B/assayed sponge, respectively). Additionally, we explored the use of plasmid DNA with the CD-Ada matrix and observed PDGF-B expression in vivo. Our results show that this new delivery system provides a safe, efficient, and adaptable medium for both viral and non-viral gene delivery.

Journal of Biological …, 1995

Journal of virology, 1982

The polypeptide coding assignments for the five messengers of the 18S size class of Newcastle dis... more The polypeptide coding assignments for the five messengers of the 18S size class of Newcastle disease virus (NDV) RNA have been determined by cell-free translation of individual RNAs separated by gel electrophoresis. Listed in order of their decreasing electrophoretic mobilities in acid agarose-urea gels, the coding assignments of the RNAs were as follows: RNA 1, M protein; RNA 2, P protein; RNA 3, NP; RNA 4, F glycoprotein; and RNA 5, HN glycoprotein. RNA 2 also directed the synthesis of 33- and 36-kilodalton proteins, which were tentatively identified as being overlapping segments of the P protein. The 33- and 36-kilodalton polypeptides could be detected in infected cells, but not in purified virions of NDV. Since the other unique NDV RNA, a 35S species, has been shown previously to encode the viral L protein, these results complete the coding assignments of the six known NDV mRNAs.

Session topics include: Comparative Biology of Stress Proteins and Longevity Compartment-specific... more Session topics include:
Comparative Biology of Stress Proteins and Longevity
Compartment-specific and Extracellular HSPs and Other Molecular Chaperones
Global Regulatory Networks of Stress Genes
Molecular Chaperones in Development and Growth
Molecular Chaperones and Proteostasis
New Drugs and Therapeutic Interventions in Stress and Aging Related Disease
Oxidative/Reductive Stress Responses
Quality Control Mechanisms
Stress Immunity and Metabolism
Stress Management in Human Disease
Stress Responses and the Environment
Stress Responses in Women's Health

Cell Stress & Chaperones, Jul 15, 2008

Cell Stress & Chaperones, 2019

The stress response has been studied now for over 50 years and is known to have significance in t... more The stress response has been studied now for over 50 years and is known to have significance in the survival of organisms in a challenging environment and in the healthy development of all known descendants of the last common universal ancestor (LUCA). This meeting was concentrated mostly on the responses of cells and organisms to environmental and cell stress including the impact of thermal stress, which was a major theme throughout this meeting. One emphasis was on the deployment of the heat shock response that permits damage to proteins to be detected and responded to by the abundant synthesis of heat shock proteins (HSPs). Speakers and presenters of posters responded to the questions of how are the HSPs rapidly induced by stressors? By which mechanisms are they are regulated in the cell by protein-protein interactions or posttranslational modification? And, what are the consequences when these abundantly expressed proteins escape the confines of the cell and influence the extracellular microenvironment? Key among the questions was how does stress influence longevity and aging and what happens in terms of disease control (malignant, neurodegenerative) when stress responses become compromised? In this context, many presenters addressed the question of pharmacologically modifying the heat shock response and HSP functions and thus improving responses to a range of disease types.

Cell Stress & Chaperones, 2007

Heat shock protein (Hsp) 70BЈ is a human Hsp70 chaperone that is strictly inducible, having littl... more Heat shock protein (Hsp) 70BЈ is a human Hsp70 chaperone that is strictly inducible, having little or no basal expression levels in most cells. Using siRNAs to knockdown Hsp70BЈ and Hsp72 in HT-29, SW-480, and CRL-1807 human colon cell lines, we have found that the two are regulated coordinately in response to stress. We also have found that proteasome inhibition is a potent activator of Hsp70BЈ. Flow cytometry was used to assay Hsp70BЈ promoter activity in HT-29eGFP cells in this study. Knockdown of both Hsp70BЈ-and Hsp72-sensitized cells to heat stress and increasing concentrations of proteasome inhibitor. These data support the conclusion that Hsp72 is the primary Hsp70 family responder to increasing levels of proteotoxic stress, and Hsp70BЈ is a secondary responder. Interestingly ZnSO 4 induces Hsp70BЈ and not Hsp72 in CRL-1807 cells, suggesting a stressor-specific primary role for Hsp70BЈ. Both Hsp70BЈ and Hsp72 are important for maintaining viability under conditions that increase the accumulation of damaged proteins in HT-29 cells. These findings are likely to be important in pathological conditions in which Hsp70BЈ contributes to cell survival.

Molecular Biology and Evolution, 1995

Journal of Virology, 1975

We have studied the relationships among the polypeptides of Newcastle disease virus by using both... more We have studied the relationships among the polypeptides of Newcastle disease virus by using both kinetic and tryptic peptide analyses. The results of our tryptic peptide analyses suggest that there are at least six unique viral polypeptides--L, HN, FO(F), NP, M, and a 47,000-dalton polypeptide. The small virion glycopolypeptide F is related to FO, a glycopolypeptide found only in infected cells. In addition, several smaller polypeptides, including a 53,000-dalton polypeptide found both in purified virions and in infected cells, are related to the nucleocaspid protein. Kinetic analysis of each viral polypeptide reveals that all of the major viral polypeptides, with the possible exception of L, are stable after an amino acid chase. A precursor-product relationship between FO and F was not demonstrable by pulse-chase experiments. Also, almost the same relative amount of F, the putative product, was present in infected cultures after either 5 or 30 min of radioisotopic labeling. These ...

Marine Environmental Research, 1993

Cell Stress and Chaperones, 2019

Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archa... more Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archaea, bacteria, and eukaryota. sHSPs belong to the superfamily of molecular chaperones: they are components of the cellular protein quality control machinery and are thought to act as the first line of defense against conditions that endanger the cellular proteome. In plants, sHSPs protect cells against abiotic stresses, providing innovative targets for sustainable agricultural production. In humans, sHSPs (also known as HSPBs) are associated with the development of several neurological diseases. Thus, manipulation of sHSP expression may represent an attractive therapeutic strategy for disease treatment. Experimental evidence demonstrates that enhancing the chaperone function of sHSPs protects against age-related protein conformation diseases, which are characterized by protein aggregation. Moreover, sHSPs can promote longevity and healthy aging in vivo. In addition, sHSPs have been implicated in the prognosis of several types of cancer. Here, sHSP upregulation, by enhancing cellular health, could promote cancer development; on the other hand, their downregulation, by sensitizing cells to external stressors and chemotherapeutics, may have beneficial outcomes. The complexity and diversity of sHSP function and properties and the need to identify their specific clients, as well as their implication in human disease, have been discussed by many of the world's experts in the sHSP field during a dedicated workshop in Québec City, Canada, on 26-29 August 2018.

Proceedings of the …, 1992

Cell Stress & Chaperones, 2021

I retired as Editor-in-Chief on December 31, 2020, after 25 years. Cell Stress & Chaperones was m... more I retired as Editor-in-Chief on December 31, 2020, after 25 years. Cell Stress & Chaperones was my cultural baby and I watched it grow as an infant and develop into a child and young adult. But like biological children, journals are unlikely to mature into independent, fully functional adults if the parents hold their child closely for too long. One reason that I can retire comfortably at this moment is that our journal has a very talented board of Senior Editors that includes Bill Currie. Another reason is that our founding Office Manager Helen Neumann, bringing her wealth of knowledge gained from 25 years of experience, is continuing with the Journal. Bill introduced himself to me at the 1985 Cold Spring Harbor Heat Shock Meeting. I think he was surprised that I knew much of his post-doctoral work with his mentor Fredric P. White. Fred and I had met about 7 years earlier following a string of events sufficiently unique and improbable as to raise the possibility of Divine guidance....

Cell Stress and Chaperones

Cell Stress and Chaperones, 2016

The Seventh International Congress of the Cell Stress Society International (CSSI) was held as a ... more The Seventh International Congress of the Cell Stress Society International (CSSI) was held as a joint meeting with the newly organized committee of Stress Physiology, the Chinese Association for Physiological Sciences (CAPS). There were over 200 colleagues and their students in attendance from 22 different countries. The topics of the congress were core scientific areas in the field of stress and health. The keynote speakers were Fu-Chu He (China), E.R. (Ron) de Kloet (The Netherlands), and Kazuhiro Nagata (Japan). The CSSI Medallion for Career Achievement in the cell stress and chaperones field was awarded to Kazutoshi Mori (Japan). Twelve student post awards were given in recognition of a very high quality poster session. In the tradition of this series of congresses, cultural events were an important part of the program. In addition, participants became better acquainted during trips to the ancient shopping street, an evening at the Chinese opera, and a lesson in Tai Chi from a master. The first groups of CSSI Fellows and Senior Fellows were presented their rosettes and certificates during the congress.

Results and Problems in Cell Differentiation, 1991

ABSTRACT

Heat Shock Proteins, 2015

HSP27 is essential for mammalian cell movement. To further explore the effects of heat shock and ... more HSP27 is essential for mammalian cell movement. To further explore the effects of heat shock and the mechanistic role of HSP27, we have initiated a study using a well-established model of rapidly moving cells, the fi sh keratocyte. Here we report that heat shock causes a decrease in cell speed. Since changes in cell morphology can drastically affect cell movement, we also monitored changes in cell morphology. Heat shock caused a decrease in the number of polar cells and an increase in those with one stuck adherent edge, indicating the occurrence of both cytoskeletal reorganization and increased adhesion to substrata. Analyses of HSP27 levels using Western blots showed they were relatively high in keratocytes prior to heat shock and remained high afterward. In contrast, Western blot analysis of HSP70 showed that it was induced strongly by heat shock, indicating that fi sh keratocytes mounted a robust heat shock response. Surprisingly, given the propensity of HSP27 to localize in nuclear/perinuclear regions following heat shock, the location of HSP27 in fi sh keratocytes was unchanged as shown by indirect immunostaining with anti-HSP27 antibodies. Fluorescence intensities of immunostained images of cells before and after heat shock were quantifi ed using Image J software. The results of this analysis showed that fl uorescence intensity decreased following heat shock, suggesting changes in HSP27 that affected antibody recognition. Possible roles for HSP27 in regulating actin fi lament dynamics, cell speed and morphology are discussed.

Biocompatible matrices, such as bovine collagen, have demonstrated usefulness in delivering gene ... more Biocompatible matrices, such as bovine collagen, have demonstrated usefulness in delivering gene therapy vectors that express growth factors to local environments for tissue repair. Unlike animal derived matrices, we have developed a new synthetic matrix consisting of a linear cyclodextrin-polyethyleneglycol co-polymer that is non-covalently cross-linked with di-adamantane-polyethyleneglycol via inclusion complex formation between adamantane and cyclodextrin (CD-Ada). We performed both in vitro and in vivo experiments for biocompatibility and localized transgene expression using a recombinant adenovirus (rAd) vector containing either the reporter gene, GFP, or the therapeutic gene, PDGF-B. In vitro results demonstrated cell migration, adenoviral transduction, and gene expression with no visible signs of toxicity in human skin fibroblasts. Qualitative gene expression from the CD-Ada containing rAd was delayed by approximately two days when compared to collagen, but the level of expression was greater over a longer period of time. In vivo experiments demonstrated gene expression after local delivery to mouse skin using rAd-GFP in CD-Ada. Again, the expression was slightly delayed but duration of expression was comparable to collagen. Expression studies using rAd-PDGF-B, were performed in the rat polyvinyl alcohol sponge model and showed comparable quantitative DNA and RNA levels between CD-Ada and collagen (DNA: 4.1 • 10 10 and 4.5 • 10 10 MEQ of PDGF-B/assayed sponge, respectively; RNA: 7.0 • 10 8 and 3.2 • 10 8 MEQ of PDGF-B/assayed sponge, respectively). Additionally, we explored the use of plasmid DNA with the CD-Ada matrix and observed PDGF-B expression in vivo. Our results show that this new delivery system provides a safe, efficient, and adaptable medium for both viral and non-viral gene delivery.

Journal of Biological …, 1995

Journal of virology, 1982

The polypeptide coding assignments for the five messengers of the 18S size class of Newcastle dis... more The polypeptide coding assignments for the five messengers of the 18S size class of Newcastle disease virus (NDV) RNA have been determined by cell-free translation of individual RNAs separated by gel electrophoresis. Listed in order of their decreasing electrophoretic mobilities in acid agarose-urea gels, the coding assignments of the RNAs were as follows: RNA 1, M protein; RNA 2, P protein; RNA 3, NP; RNA 4, F glycoprotein; and RNA 5, HN glycoprotein. RNA 2 also directed the synthesis of 33- and 36-kilodalton proteins, which were tentatively identified as being overlapping segments of the P protein. The 33- and 36-kilodalton polypeptides could be detected in infected cells, but not in purified virions of NDV. Since the other unique NDV RNA, a 35S species, has been shown previously to encode the viral L protein, these results complete the coding assignments of the six known NDV mRNAs.

Molecular and cellular biology, 1990

A novel form of regulation of expression of a vertebrate heat shock gene is described. A cDNA clo... more A novel form of regulation of expression of a vertebrate heat shock gene is described. A cDNA clone encoding human Hsp27 was shown to specifically recognize chicken Hsp23 RNA by Northern (RNA) blot analysis and hybrid-select translation. This probe was then used to measure chicken hsp23 gene activity in control and heat-stressed cells. The hsp23 gene(s) was transcriptionally active in non-heat-stressed cells, and its rate of transcription did not increase significantly upon heat shock. Cytoplasmic Hsp23 mRNA, which was metabolically very stable in nonstressed cells, underwent a fourfold increase in amount after a 1-h heat shock, resulting in a twofold increase in Hsp23 mRNA in polysomes. Hsp23 mRNA was relatively abundant and translationally active even in non-heat-shocked cells. Taken together, these data implicated posttranscriptional nuclear events as an important control point for induction of Hsp23 RNA transcripts. The protein half-life of Hsp23 increased from approximately 2 h...

Journal of virology, 1981

A unique abundant protein, designated P by analogy to the putative polymerase proteins of other p... more A unique abundant protein, designated P by analogy to the putative polymerase proteins of other paramyxoviruses, was identified in purified Newcastle disease virus. Under nonreducing conditions the P proteins could be separated from other viral proteins on ...