Bert W. O'Malley

Last updated
Bert W. O'Malley
O'malley.jpg
Born
Pittsburgh, Pennsylvania, U.S.
NationalityAmerican
Alma materUniversity of Pittsburgh (BSc, MD), Duke University (Residency in Internal Medicine), National Institutes of Health (Research Training)
Known forDiscovery of coactivators in gene expression regulation, Advances in understanding hormone action at the molecular level, Development of therapeutic strategies for cancer and metabolic diseases
AwardsNational Medal of Science (2008), Elected member of the National Academies of Sciences, Medicine, and Inventors, Over 65 honors and major awards
Scientific career
FieldsMolecular Endocrinology, Gene Regulation, Steroid Receptor-Coactivator Action
InstitutionsVanderbilt University, Baylor College of Medicine

Bert W. O'Malley was born in 1936 in the Garfield section of Pittsburgh, Pennsylvania. He received his early education at Catholic primary schools and Central Catholic High School, before pursuing higher education at the University of Pittsburgh, where he completed both his undergraduate and medical studies, graduating first in his class. [1] It was here that he met Sally, who would become his wife and lifelong partner. The couple went on to have four children. [2]

Contents

After completing his medical degree, O'Malley moved to Duke University for residency training in Internal Medicine, followed by advanced clinical endocrine and research training at the National Institutes of Health's National Cancer Institute (NIH-NCI). [3] During his time at NIH, O'Malley made significant contributions to endocrinology by utilizing the chick oviduct as a model to study how female sex steroids induce the synthesis of ovalbumin and avidin proteins, thus advancing the understanding of hormone regulation in endocrine organs. [4] [5]

In 1969, O'Malley joined Vanderbilt University as the Lucious Birch Professor. [6] His research during the 1960s, a time of various competing theories on hormone function in cells, led him to be the first to demonstrate in 1972 that hormones act on DNA to induce changes in gene expression and specific mRNAs, which in turn direct all target cell functions and growth. This ground-breaking work provided clarity in the field and set the stage for future research on hormone action mediated gene expression and pharmaceutical development. [7] [8]

O'Malley's career took another significant turn in 1972 when he moved to Baylor College of Medicine in Houston, taking on the role of the Tom Thompson Distinguished Leadership Professor and Chair of Molecular and Cellular Biology. In 2019, he assumed the position of Chancellor at Baylor College of Medicine, marking a distinguished career in medical research and education. Throughout his career, O'Malley's contributions have been instrumental in advancing the understanding of hormone action at the molecular level, impacting both basic sciences and clinical practices. [3]

Middle Scientific Career

In his research, he proposed that nuclear receptors function as transcription factors that regulate mRNA production in target cells in response to intracellular hormones. This hypothesis led him to uncover the detailed mechanisms activating steroid nuclear receptors (NRs) through the discovery of previously unidentified coactivators necessary for receptor-dependent gene transcription. [9] In 1995, he successfully cloned the first coactivator, SRC-1, marking a significant advancement in the field. [10] His identification of coactivators as critical elements in the regulation of the mammalian genome has significantly enhanced our molecular understanding of hormone action, including the effects of agonist and antagonist ligands and selective estrogen receptor modulators (SERMs). [11]

Over the course of more than 300 subsequent scholarly articles, his work underscored the crucial role of coactivators in a wide range of physiological processes and diseases, including genetics, reproduction, metabolism, inflammation, cardiovascular and central nervous system (CNS) functions, with a particular emphasis on cancer research. [12] His laboratory's publication of the first structures of full-length estrogen receptor (ER)/SRC3/p300, androgen receptor (AR)/SRC2/p300, and progesterone receptor (PR)/SRC3/p300 complexes bound to DNA are considered landmark contributions to the field. [13] Following these discoveries, he further explored the potential of coactivator- targeted approaches in medicine.

Later Career

Bert O'Malley's early research greatly advanced the understanding of nuclear coactivator proteins and their role in the dysfunction of transcription processes associated with metabolic diseases, degeneration of the heart and brain, and notably, cancers. [14] His work elucidated the structure and function of mammalian coregulator complexes, revealing their critical roles in transcription, oncogenic diseases, and tissue repair. [15] This research paved the way for exploring coactivator-dependent therapies, with his laboratory discovering small molecule drugs aimed at regulating coactivators to address conditions such as cancer, metabolic diseases, stroke, and heart failure. [16]

Further investigations led O'Malley to identify a crucial function of the SRC-3 coactivator in immune T-regulatory cells, which play a protective role against autoimmunity but can also suppress the immune system's ability to kill cancer cells. [17] His team developed a mouse model with the SRC-3 gene specifically deleted in T-regulatory cells, finding that this modification allowed T-conventional attack cells to effectively eliminate tumors. [18] His lab's breakthrough demonstrated that these genetically modified animals exhibited a remarkable resistance to major cancers throughout their lifespan. O'Malley's group went on to pioneer a coactivator-centric adoptive cell transfer technique aimed at cancer treatment, showing that a single injection of SRC-3-deleted T-regulatory cells could permanently eliminate existing cancers without detectable toxicity. [19] This method has been patented and will be developed by CoRegen-BCM for clinical application. [20]

Currently, O'Malley leads the Baylor Center for Coregulator Research, along with Drs. David Lonard, Sang-Jun Han, and Clifford Dacso. His contributions to the field of Endocrinology have earned him recognition as the Father of Molecular Endocrinology. [3]

He is an elected member of the National Academies: of Sciences, of Medicine, and of Inventors. O'Malley has received over 65 honors and major awards, including the National Medal of Science in 2008. Throughout his career, he has mentored more than 220 scientists, published over 750 papers, and holds 33 patents related to gene regulation, molecular endocrinology, steroid receptor-coactivator action, and molecular and cell-based medical therapies.

Publications

Early Career:

1. Means AR, Comstock JP, Rosenfeld GC, O'Malley BW. Ovalbumin messenger RNA of chick oviduct: partial characterization, estrogen dependence, and translation in vitro. Proc Natl Acad Sci U S A. 1972; 69(5):1146-50. [21]

2. Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995;270(5240):1354. [22]

Middle Career:

3. Yi P, Wang Z, Feng Q, Pintilie, GD, Foulds CF, Lanz, RB, Ludtke SJ, Schmid MF, Chiu W, O’Malley BW. The Structure of A Biologically Active Estrogen Receptor-Coactivator Complex on DNA. Molec. Cell. 2015.19;57(6):1047-58. [23]

4. Song X, Chen H, Zhang C, Yu Y, Chen Z, Liang H, Van Buren II G, McElhany AL, Fisher WE, Lonard DM, O’Malley BW, Wang J. SRC-3 Inhibition Blocks Tumor Growth of Pancreatic Ductal Adenocarcinoma Cancer Lett. 2019 Feb 1; 442: 310–319. [24]

Later Career:

5. Mullany LK, Rohira AD, Leach JP, Kim JH, Monroe TO, Ortiz AR, Stork B, Gaber MW, Sarkar P, Silora AG, Rosengart TK, York B, Song Y, Dacso CC, Lonard DM, Martin JF, O’Malley BW. A Steroid Receptor Coactivator Stimulator (MCB-613) Prevents Adverse Remodeling After Myocardial Infarction. Proc Natl Acad Sci USA. 2020 117: 31353-64. [25]

6. Han SJ, Jain P, Gilad Y, Xia Y, Sung N, Park MJ, Dean AM, Lanz RB, Xu J, Dacso CC, Lonard DM, O'Malley BW. Tumor Eradication by Steroid Receptor Coactivator-3 Deleted Regulatory T Cells. PNAS 2023; vol.120 May 30. [26]

Related Research Articles

A hormone receptor is a receptor molecule that binds to a specific hormone. Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other receptors for various ligands, such as fatty acids and prostaglandins. Hormone receptors are of mainly two classes. Receptors for peptide hormones tend to be cell surface receptors built into the plasma membrane of cells and are thus referred to as trans membrane receptors. An example of this is Actrapid. Receptors for steroid hormones are usually found within the protoplasm and are referred to as intracellular or nuclear receptors, such as testosterone. Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.

<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

<span class="mw-page-title-main">Progesterone receptor</span> Cytoplasmic receptor protein found inside cells

The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone.

<span class="mw-page-title-main">Androgen receptor</span> Mammalian protein found in humans

The androgen receptor (AR), also known as NR3C4, is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.

<span class="mw-page-title-main">Selective progesterone receptor modulator</span>

A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor (PR), the biological target of progestogens like progesterone. A characteristic that distinguishes such substances from full receptor agonists and full antagonists is that their action differs in different tissues, i.e. agonist in some tissues while antagonist in others. This mixed profile of action leads to stimulation or inhibition in tissue-specific manner, which further raises the possibility of dissociating undesirable adverse effects from the development of synthetic PR-modulator drug candidates.

<span class="mw-page-title-main">Coactivator (genetics)</span> Class of proteins involved in regulation of transcription

A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.

<span class="mw-page-title-main">PELP-1</span> Mammalian protein found in Homo sapiens

Proline-, glutamic acid- and leucine-rich protein 1 (PELP1) also known as modulator of non-genomic activity of estrogen receptor (MNAR) and transcription factor HMX3 is a protein that in humans is encoded by the PELP1 gene. is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors and a coactivator for estrogen receptors.

<span class="mw-page-title-main">Estrogen receptor alpha</span> Protein-coding gene in the species Homo sapiens

Estrogen receptor alpha (ERα), also known as NR3A1, is one of two main types of estrogen receptor, a nuclear receptor that is activated by the sex hormone estrogen. In humans, ERα is encoded by the gene ESR1.

<span class="mw-page-title-main">Nuclear receptor</span> Protein

In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism.

<span class="mw-page-title-main">Nuclear receptor coactivator 1</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor coactivator 1 (NCOA1), also called steroid receptor coactivator-1 (SRC-1), is a transcriptional coregulatory protein that contains several nuclear receptor–interacting domains and possesses intrinsic histone acetyltransferase activity. It is encoded by the gene NCOA1.

<span class="mw-page-title-main">Nuclear receptor coactivator 3</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).

<span class="mw-page-title-main">Selective androgen receptor modulator</span> Class of pharmaceutical drugs

Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate the androgen receptor in specific tissues, promoting muscle and bone growth while having less effect on male reproductive tissues like the prostate gland.

<span class="mw-page-title-main">Estrogen receptor beta</span> Protein-coding gene in the species Homo sapiens

Estrogen receptor beta (ERβ) also known as NR3A2 is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by the ESR2 gene.

<span class="mw-page-title-main">Estrogen-related receptor alpha</span> Protein-coding gene in the species Homo sapiens

Estrogen-related receptor alpha (ERRα), also known as NR3B1, is a nuclear receptor that in humans is encoded by the ESRRA gene. ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha, but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα. Currently, ERRα is considered an orphan nuclear receptor.

<span class="mw-page-title-main">Thyroid hormone receptor alpha</span> Protein-coding gene in the species Homo sapiens

Thyroid hormone receptor alpha (TR-alpha) also known as nuclear receptor subfamily 1, group A, member 1 (NR1A1), is a nuclear receptor protein that in humans is encoded by the THRA gene.

<span class="mw-page-title-main">SRA1</span> Protein-coding gene in the species Homo sapiens

Steroid receptor RNA activator 1 also known as steroid receptor RNA activator protein (SRAP) is a protein that in humans is encoded by the SRA1 gene. The mRNA transcribed from the SRA1 gene is a component of the ribonucleoprotein complex containing NCOA1. This functional RNA also encodes a protein.

Nuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily. A comprehensive database of coregulators for nuclear receptors and other transcription factors was previously maintained at the Nuclear Receptor Signaling Atlas website which has since been replaced by the Signaling Pathways Project website.

Menerba, also known as Menopause Formula 101 (MF-101), is a botanical drug candidate that acts as a selective estrogen receptor modulator (SERM) which is being studied for its potential to relieve hot flashes associated with menopause. Menerba, an estrogen receptor beta (ERβ) agonist (ERBA), is part of a new class of receptor subtype-selective estrogens, which is selective in transcriptional regulation to one of the two known estrogen receptor (ER) subtypes. Menerba consists of 22 herbs that have been used historically in traditional Chinese medicine.

<span class="mw-page-title-main">ERX-11</span> Chemical compound

ERX-11, also known as ERα coregulator-binding modulator-11, is a novel antiestrogen and experimental hormonal antineoplastic agent which is being researched for the potential treatment of estrogen receptor-positive breast cancer. It is not a competitive antagonist of the estrogen receptor (ER) like conventional antiestrogens such as tamoxifen or fulvestrant; instead of binding to the ligand-binding site of the ER, ERX-11 interacts with a different part of the ERα and blocks protein–protein interactions of the ERα with coregulators that are necessary for the receptor to act and regulate gene expression. It was designed to bind to the coregulator binding region of the ERα and inhibit the ERα/coactivator interaction, although its precise binding site and mode of action have yet to be fully elucidated and understood. Nonetheless, it is clear that ERX-11 binds within the AF-2 domain of the ERα.

Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.

References

  1. ↑ "Request Rejected". www.225.pitt.edu. Retrieved 2024-04-05.
  2. ↑ Kumar, T Rajendra (2018-02-15). "An interview with Professor Bert O' Malley". Biology of Reproduction. pp. 269–270. doi:10.1093/biolre/ioy046. PMID   29462460 . Retrieved 2024-04-05.
  3. 1 2 3 "Bert W O'Malley, M.D. | BCM". www.bcm.edu. Retrieved 2024-04-05.
  4. ↑ "jbc.org".
  5. ↑ Hughes, Mark R.; Compton, John G.; Schrader, William T.; O'Malley, Bert W. (1981-04-01). "Interaction of the chick oviduct progesterone receptor with deoxyribonucleic acid". Biochemistry. 20 (9): 2481–2491. doi:10.1021/bi00512a019. ISSN   0006-2960. PMID   7236615.
  6. ↑ "Department of Molecular and Cellular Biology celebrates 50 years". BCM Family. 2023-01-25. Retrieved 2024-04-05.
  7. ↑ Tata, Jamshed R. (June 2005). "One hundred years of hormones: A new name sparked multidisciplinary research in endocrinology, which shed light on chemical communication in multicellular organisms". EMBO Reports. 6 (6): 490–496. doi:10.1038/sj.embor.7400444. ISSN   1469-221X. PMC   1369102 . PMID   15940278.
  8. ↑ O’Malley, Bert W. (2005-06-01). "A Life-Long Search for the Molecular Pathways of Steroid Hormone Action". Molecular Endocrinology. 19 (6): 1402–1411. doi:10.1210/me.2004-0480. ISSN   0888-8809. PMID   15914709.
  9. ↑ Johnson, Amber B.; O’Malley, Bert W. (2012-01-30). "Steroid receptor coactivators 1, 2, and 3: Critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy". Molecular and Cellular Endocrinology. Nuclear Receptor Structure: Dynamics and Function. 348 (2): 430–439. doi:10.1016/j.mce.2011.04.021. ISSN   0303-7207. PMC   3202666 . PMID   21664237.
  10. ↑ Wang, Ying; Lonard, David M.; Yu, Yang; Chow, Dar-Chone; Palzkill, Timothy G.; O'Malley, Bert W. (2011-12-01). "Small Molecule Inhibition of the Steroid Receptor Coactivators, SRC-3 and SRC-1". Molecular Endocrinology. 25 (12): 2041–2053. doi:10.1210/me.2011-1222. ISSN   0888-8809. PMC   3231837 . PMID   22053001.
  11. ↑ Jordan, V. Craig; O'Malley, Bert W. (2007-12-20). "Selective Estrogen-Receptor Modulators and Antihormonal Resistance in Breast Cancer". Journal of Clinical Oncology. 25 (36): 5815–5824. doi:10.1200/JCO.2007.11.3886. ISSN   0732-183X. PMID   17893378.
  12. ↑ "Bert W. O'Malley". scholar.google.com. Retrieved 2024-04-05.
  13. ↑ Varisli, Lokman; Dancik, Garrett M.; Tolan, Veysel; Vlahopoulos, Spiros (January 2023). "Critical Roles of SRC-3 in the Development and Progression of Breast Cancer, Rendering It a Prospective Clinical Target". Cancers. 15 (21): 5242. doi: 10.3390/cancers15215242 . ISSN   2072-6694. PMC   10648290 . PMID   37958417.
  14. ↑ Dasgupta, Subhamoy; O'Malley, Bert W. (2014-10-01). "Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology". Journal of Molecular Endocrinology. 53 (2): R47–R59. doi:10.1530/JME-14-0080. ISSN   1479-6813. PMC   4152414 . PMID   25024406.
  15. ↑ McKenna, Neil J.; Nawaz, Zafar; Tsai, Sophia Y.; Tsai, Ming-Jer; O’Malley, Bert W. (1998-09-29). "Distinct steady–state nuclear receptor coregulator complexes exist in vivo". Proceedings of the National Academy of Sciences. 95 (20): 11697–11702. Bibcode:1998PNAS...9511697M. doi: 10.1073/pnas.95.20.11697 . ISSN   0027-8424. PMC   21703 . PMID   9751728.
  16. ↑ "apps.dtic.mil".
  17. ↑ Han, Sang Jun; Jain, Prashi; Gilad, Yosef; Xia, Yan; Sung, Nuri; Park, Mi Jin; Dean, Adam M.; Lanz, Rainer B.; Xu, Jianming; Dacso, Clifford C.; Lonard, David M.; O'Malley, Bert W. (2023-06-06). "Steroid receptor coactivator 3 is a key modulator of regulatory T cell–mediated tumor evasion". Proceedings of the National Academy of Sciences. 120 (23): e2221707120. Bibcode:2023PNAS..12021707H. doi:10.1073/pnas.2221707120. ISSN   0027-8424. PMC   10266015 . PMID   37253006.
  18. ↑ Rodríguez, Ana (2023-06-08). "Eliminating gene SRC-3 in immune cells triggers effective long-lasting anti-cancer response". Baylor College of Medicine Blog Network. Retrieved 2024-04-05.
  19. ↑ Wang, Lei; Lonard, David M.; O’Malley, Bert W. (2016-08-01). "The Role of Steroid Receptor Coactivators in Hormone Dependent Cancers and Their Potential as Therapeutic Targets". Hormones and Cancer. 7 (4): 229–235. doi:10.1007/s12672-016-0261-6. ISSN   1868-8500. PMC   4930410 . PMID   27125199.
  20. ↑ "SRC-3: CoRegen's revolutionary approach to cancer". Drug Target Review. Retrieved 2024-04-05.
  21. ↑ Chan, Lawrence; Means, Anthony R.; O'Malley, Bert W. (June 1973). "Rates of Induction of Specific Translatable Messenger RNAs for Ovalbumin and Avidin by Steroid Hormones". Proceedings of the National Academy of Sciences. 70 (6): 1870–1874. Bibcode:1973PNAS...70.1870C. doi: 10.1073/pnas.70.6.1870 . ISSN   0027-8424. PMC   433615 . PMID   4515943.
  22. ↑ Yi, P.; Wang, Z.; Feng, Q.; Pintilie, G. D.; Foulds, C. E.; Lanz, R. B.; Ludtke, S. J.; Schmid, M. F.; Chiu, W.; O'Malley, B. W. (2015). "ncbi.nlm.nih.gov". Molecular Cell. 57 (6): 1047–1058. doi:10.1016/j.molcel.2015.01.025. PMC   4369429 . PMID   25728767.
  23. ↑ Yi, P.; Wang, Z.; Feng, Q.; Pintilie, G. D.; Foulds, C. E.; Lanz, R. B.; Ludtke, S. J.; Schmid, M. F.; Chiu, W.; O'Malley, B. W. (2015). "ncbi.nlm.nih.gov". Molecular Cell. 57 (6): 1047–1058. doi:10.1016/j.molcel.2015.01.025. PMC   4369429 . PMID   25728767.
  24. ↑ Song, X.; Chen, H.; Zhang, C.; Yu, Y.; Chen, Z.; Liang, H.; Van Buren g, I. I.; McElhany, A. L.; Fisher, W. E.; Lonard, D. M.; O'Malley, B. W.; Wang, J. (2018). "ncbi.nlm.nih.gov". Cancer Letters. 442: 310–319. doi:10.1016/j.canlet.2018.11.012. PMC   6311429 . PMID   30423406.
  25. ↑ "europepmc.org".
  26. ↑ Han, Sang Jun; Jain, Prashi; Gilad, Yosef; Xia, Yan; Sung, Nuri; Park, Mi Jin; Dean, Adam M.; Lanz, Rainer B.; Xu, Jianming; Dacso, Clifford C.; Lonard, David M.; O'Malley, Bert W. (2023-06-06). "Steroid receptor coactivator 3 is a key modulator of regulatory T cell–mediated tumor evasion". Proceedings of the National Academy of Sciences. 120 (23): e2221707120. Bibcode:2023PNAS..12021707H. doi:10.1073/pnas.2221707120. ISSN   0027-8424. PMC   10266015 . PMID   37253006.
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