Stanley M. Hollenberg

Oregon Health & Science University

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Co-Authors

Ronald M. Evans

Salk Institute for Biological Studies

Michael G. Rosenfeld

Howard Hughes Medical Institute

Cary Weinberger

National Institute of Environmental Health Sciences

Vincent Giguère

McGill University

Tiffani L. Howard

Oregon Health & Science University

Estelita S. Ong

Wellcome Sanger Institute

Harold Weintraub

Philadelphia College of Osteopathic Medicine

Joachim L. Weickmann

EKOS Corporation

Andrew B. Lassar

Harvard University

Stephen J. Tapscott

Fred Hutch Cancer Center

Cooperative Institutions

Howard Hughes Medical Institute

Fred Hutch Cancer Center

University of California, San Diego

Salk Institute for Biological Studies

Oregon Health & Science University

Vollum Institute

National Institutes of Health

University of Washington

University of California, Los Angeles

Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa

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Regional chromosomal assignment of the human glucocorticoid receptor gene to 5q31

Human Genetics (1989)

A. Theriault E. Boyd Stephen Harrap Stanley M. Hollenberg J. M. Connor

Human genetics

Metabolic disease

10.1007/bf00285175

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Citations (55)

CHMP1 is a novel nuclear matrix protein affecting chromatin structure and cell-cycle progression

Journal of Cell Science (2001)

Daniel Stauffer Tiffani L. Howard Thihan Nyun Stanley M. Hollenberg

The Polycomb-group (PcG) is a diverse set of proteins required for maintenance of gene silencing during development. In a screen for conserved partners of the PcG protein Polycomblike (Pcl), we have identified a new protein, human CHMP1 (CHromatin Modifying Protein; CHarged Multivesicular body Protein), which is encoded by an alternative open reading frame in the PRSM1 gene and is conserved in both complex and simple eukaryotes. CHMP1 contains a predicted bipartite nuclear localization signal and distributes as distinct forms to the cytoplasm and the nuclear matrix in all cell lines tested. We have constructed a stable HEK293 cell line that inducibly overexpresses CHMP1 under ecdysone control. Overexpressed CHMP1 localizes to a punctate subnuclear pattern, encapsulating regions of nuclease-resistant, condensed chromatin. These novel structures are also frequently surrounded by increased histone H3 phosphorylation and acetylation. CHMP1 can recruit a PcG protein, BMI1, to these regions of condensed chromatin and can cooperate with co-expressed vertebrate Pcl in a Xenopus embryo PcG assay; this is consistent with a role in PcG function. In combination, these observations suggest that CHMP1 plays a role in stable gene silencing within the nucleus.

Nuclear matrix

Scaffold/matrix attachment region

Nuclear lamina

10.1242/jcs.114.13.2383

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Citations (111)

Identification of two regions of the human glucocorticoid receptor hormone binding domain that block activation.

PubMed (1989)

Stanley M. Hollenberg Vincent Giguère Ronald M. Evans

The steroid-binding domain of the human glucocorticoid receptor has a dominant, negative influence over the activity of the remainder of the molecule. We have determined sequences within this domain that are responsible for this inhibition by creating truncations and internal deletions which remove part or all of the ligand-binding domain. Two apparently unrelated sequences within this region are shown to block the ability to stimulate transcription when fused to the carboxyl terminus of a functional, hormone-independent receptor derivative. These results support the possibility of two distinct protein-binding sites within the steroid-binding domain.

Hormone response element

Steroid hormone

Source

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Citations (23)

Muscle-specific transcriptional activation by MyoD.

Genes & Development (1991)

H Weintraub Varavani Dwarki Inder M. Verma Robert L. Davis Stanley M. Hollenberg

We focus on the mechanism by which MyoD activates transcription. Previous experiments showed that when the 13-amino-acid basic region of E12 replaced the corresponding basic region of MyoD, the resulting MyoD-E12Basic chimeric protein could bind specifically to muscle-specific enhancers in vitro and form dimers with E12, but could not activate a cotransfected reporter gene or convert 10T1/2 cells to muscle. Here we show that back mutation of this chimeric protein (with the corresponding residues in MyoD) re-establishes activation, and we identify a specific alanine involved in increasing DNA binding and a specific threonine required for activation. Using a reporter gene containing MyoD-binding sites located downstream from the transcription start site, we show that MyoD-E12Basic can bind in vivo and thereby inhibit expression of the reporter. In vivo binding is also supported by the fact that the addition of the "constitutive" VP16 activation domain to MyoD-E12Basic restores full trans-activation potential. The normal MyoD-activation domain maps within the amino-terminal 53 residues and can be functionally replaced by the activation domain of VP16. The activity of the MyoD-activation domain is dramatically elevated when deletions are made almost anywhere in the rest of the MyoD molecule, suggesting that the activation domain in MyoD is usually masked. Surprisingly, MyoD-E12Basic can activate transcription in CV1 and B78 cells (but not in 10T1/2 or 3T3 cells), suggesting that the activation function of the basic domain requires a specific factor present in CV1 and B78 cells. We propose that to function, the masked MyoD-activation domain requires the participation of a second factor that recognizes the basic region. We refer to such a factor as a recognition factor.

PITX2

MyoD Protein

10.1101/gad.5.8.1377

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Citations (349)

Cooperative and Positional Independent trans-Activation Domains of the Human Glucocorticoid Receptor

Cold Spring Harbor Symposia on Quantitative Biology (1988)

Ronald M. Evans Stanley M. Hollenberg

A central focus of eukaryotic molecular biology is the elucidation of molecules and mechanisms that mediate specific gene regulation in a precise temporal and spatial fashion. The identification of transcriptional factors with the ability to recognize and to bind to specific DNA sequences is critical for elucidating these mechanisms. The action of steroid and thyroid hormones is mediated by nuclear receptors that are ligand-dependent transcription factors (Evans 1988). Analysis of these receptors is thus important for understanding the molecular basis of transcriptional control, as well as for providing insight into how an individual transcription factor contributes to cell identity and function.

PELP-1

Transcription

10.1101/sqb.1988.053.01.092

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Citations (11)

Hormone-Dependent Transcriptional Activation by Thyroid Hormone Receptors: Functional Homology with Steroid Hormone Receptors

Springer eBooks (1989)

Stanley M. Hollenberg Catherine C. Thompson Ronald M. Evans

Thyroid hormone receptor

Steroid hormone

Homology

Sex hormone receptor

10.1007/978-3-642-75022-9_5

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Citations (1)

A positive genetic selection for disrupting protein–protein interactions: Identification of CREB mutations that prevent association with the coactivator CBP

Proceedings of the National Academy of Sciences (1996)

Hsiu-Ming Shih Phyllis S. Goldman Anthony J. DeMaggio Stanley M. Hollenberg Richard H. Goodman

The Escherichia coli tet -repressor (TetR) operator system was used to develop a variation of the yeast two-hybrid assay in which disruptions of protein–protein interactions can be identified by a positive selection. This assay, designated the “split-hybrid system,” contains a two-component reporter. The first component contains LexA binding sites upstream of the TetR gene and the second contains TetR operator binding sites upstream of HIS3 . Interaction of one protein fused to the LexA DNA binding domain with a second protein fused to the VP16 activation domain results in TetR expression. TetR subsequently binds to the tet operators, blocking the expression of HIS3 and preventing yeast growth in media lacking histidine. The utility of the split-hybrid system was analyzed by examining the phosphorylation-dependent interaction of CREB and its coactivator CREB binding protein (CBP). CREB and CBP associate through an interaction that depends upon CREB phosphorylation at Ser-133. Mutation of this phosphorylation site prevents yeast growth in the standard two-hybrid assay but allows growth in the split-hybrid strains. The split-hybrid system was used to identify other CREB mutations that disrupt its association with CBP. These mutations localized around the site of CREB phosphorylation, indicating that only a small portion of the CREB activation domain is required for CBP interaction. The yeast split-hybrid system should be useful in identifying mutations, proteins, peptides, and drugs that disrupt protein–protein interactions.

TetR

Repressor lexA

CREB-binding protein

Two-hybrid screening

10.1073/pnas.93.24.13896

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Citations (103)

The myoD Gene Family: Nodal Point During Specification of the Muscle Cell Lineage

Science (1991)

Harold Weintraub Robert L. Davis Stephen J. Tapscott Matthew Thayer Michael Krause

The myoD gene converts many differentiated cell types into muscle. MyoD is a member of the basic-helix-loop-helix family of proteins; this 68-amino acid domain in MyoD is necessary and sufficient for myogenesis. MyoD binds cooperatively to muscle-specific enhancers and activates transcription. The helix-loop-helix motif is responsible for dimerization, and, depending on its dimerization partner, MyoD activity can be controlled. MyoD senses and integrates many facets of cell state. MyoD is expressed only in skeletal muscle and its precursors; in nonmuscle cells myoD is repressed by specific genes. MyoD activates its own transcription; this may stabilize commitment to myogenesis.

PITX2

Basic helix-loop-helix

MyoD Protein

10.1126/science.1846704

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Citations (1,571)

Domain structure of human glucocorticoid receptor and its relationship to the v-erb-A oncogene product

Nature (1985)

Cary Weinberger Stanley M. Hollenberg Michael G. Rosenfeld Ronald M. Evans

Steroid hormone receptor

Steroid hormone

10.1038/318670a0

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Citations (369)

Fusion of Adenovirus E1A to the Glucocorticoid Receptor by High-Resolution Deletion Cloning Creates a Hormonally Inducible Viral Transactivator

Molecular and Cellular Biology (1989)

Daniel M. Becker Stanley M. Hollenberg Robert P. Ricciardi

The 289-amino-acid E1A protein of adenovirus type 2 stimulates transcription from early viral and certain cellular promoters. Its mechanism is not known, and there exist no temperature-sensitive mutants of E1A that could help to elucidate the details of E1A transcriptional activation. To create for E1A such a conditional phenotype, we fused portions of E1A to the human glucocorticoid receptor (GR) to make transactivation by E1A dependent on the presence of dexamethasone. Nested subsets of the E1A coding region, centered around the 46-amino-acid transactivating domain, were substituted for the DNA-binding domain of the GR. One of the resulting chimeric proteins (GR/E1A-99), which included the entire E1A transactivating domain, stimulated expression from a viral early promoter (E3) exclusively in the presence of hormone. GR/E1A-99 did not transactivate a GR-responsive promoter. It therefore exhibited the promoter specificity of E1A while possessing the hormone inducibility of the GR. Two smaller chimeras that contained only portions of the E1A transactivating domain failed to transactivate E3. These three chimeras were constructed by a novel strategy, high-resolution deletion cloning. In this procedure, series of unidirectional deletions were made with exonuclease III on each side of the E1A coding region at a resolution of 1 to 2 nucleotides. The large number of in-frame fragments present in the collection of deleted clones facilitated the construction of the GR/E1A chimeras and can be used to create many additional fusions.

Transcription

Coding region

10.1128/mcb.9.9.3878-3887.1989

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