Michele Pagano (biochemist)

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Michele Pagano is an Italian-American biochemist and cancer biologist best known for his work on cell cycle control and the ubiquitin-proteasome system. He is currently the chairman of the Department of Biochemistry and Molecular Pharmacology, and the Ellen and Gerald Ritter Professor of Oncology at the New York University School of Medicine. He is also an Investigator of the Howard Hughes Medical Institute. His laboratory has played a central role in elucidating the role of a family of enzymes, the cullin-RING ubiquitin ligases (CRLs), in mediating the proteolysis of key cellular regulators. In particular, his work has uncovered the molecular mechanisms by which CRLs control cell cycle progression, signal transduction pathways, and the DNA damage response. [1] [2] [3] His work has also elucidated how the dysregulation of CRLs contributes to malignant transformation and metastasis, uncovering new therapeutic strategies. [4] [5] [6]

Contents

Education and Positions

In 1990, Pagano earned his MD and a specialty diploma in molecular endocrinology from the University of Naples Federico II, where he first conducted basic research on the estrogen receptor. After completing his medical training, he first moved to the EMBL in Heidelberg, Germany, and then to Mitotix Inc., Cambridge, Massachusetts (a pharmaceutical startup that he co-founded and that pioneered the concept of CDK inhibitors as anti-cancer agents), where he carried out his postdoctoral studies under the mentorship of Gulio Draetta. As a postdoctoral fellow, Pagano first described the importance of cyclins and CDKs for DNA replication, and then the role of the ubiquitin system in controlling the cellular levels of CDK inhibitors. In 1996, upon completion of his postdoctoral studies, Pagano moved to the New York University School of Medicine as an assistant professor. He was appointed to the position of associate professor in 1999, tenured in 2003, and became full professor in 2005. In 2015, he became the chairman of the Department of Biochemistry and Molecular Pharmacology.

Honors and service

Since 1997, Pagano's laboratory has been funded uninterruptedly by the National Institute of Health. In 2008, he was named a Howard Hughes Medical Institute Investigator. He was also the recipient of other grants and awards, including an NCI MERIT Award (2006-2017) and an NIGMS MIRA Award (2020-2025) in recognition of his achievements in cell and cancer biology. He serves on the advisory board of several pharmaceutical companies and foundations, and on the editorial board of several peer-reviewed journals in the fields of molecular oncology, cell biology, and cell signaling. Pagano has published over 200 peer-reviewed papers and has been issued 7 patents. He trained many predoctoral and postdoctoral fellows, most of whom have gone on to successful independent careers either in academia ( e.g., UPENN, Columbia University, Boston Children's Hospital, University of Illinois College of Medicine, NYU, University of Oxford, Technical University of Munich, Sapienza University of Rome, University of Verona, and University of Tokushima) or in the pharmaceutical industry. Pagano's laboratory has always been open to people from all parts of the world for training and collaborative efforts. Among the most notable visiting scientists are the Nobel laureate Avram Hershko, who spent seven summer sabbaticals in his laboratory and with whom Pagano has co-authored 10 papers, and Yosef Shiloh, known for his discovery of the checkpoint kinase ATM, who spent a sabbatical year in his lab.

Related Research Articles

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Anaphase-promoting complex</span> Cell-cycle regulatory complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">SCF complex</span>

Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.

<span class="mw-page-title-main">SKP2</span> Protein-coding gene in the species Homo sapiens

S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.

<span class="mw-page-title-main">RBX1</span> Protein-coding gene in the species Homo sapiens

RING-box protein 1 is a protein that in humans is encoded by the RBX1 gene.

<span class="mw-page-title-main">CUL4A</span> Protein-coding gene in humans

Cullin-4A is a protein that in humans is encoded by the CUL4A gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.

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

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene.

<span class="mw-page-title-main">FBXW7</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.

<span class="mw-page-title-main">CDC34</span> Protein-coding gene in the species Homo sapiens

CDC34 is a gene that in humans encodes the protein Ubiquitin-conjugating enzyme E2 R1. This protein is a member of the ubiquitin-conjugating enzyme family, which catalyzes the covalent attachment of ubiquitin to other proteins.

<span class="mw-page-title-main">CUL4B</span> Protein-coding gene in humans

Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome. CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.

<span class="mw-page-title-main">CUL3</span> Protein-coding gene in humans

Cullin 3 is a protein that in humans is encoded by the CUL3 gene.

<span class="mw-page-title-main">FBXW11</span> Protein-coding gene in the species Homo sapiens

βTrCP2 is a protein that in humans is encoded by the FBXW11 gene.

<span class="mw-page-title-main">CCNF</span> Protein-coding gene in humans

G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene.

<span class="mw-page-title-main">Cullin</span> Hydrophobic scaffold protein

Cullins are a family of hydrophobic scaffold proteins which provide support for ubiquitin ligases (E3). All eukaryotes appear to have cullins. They combine with RING proteins to form Cullin-RING ubiquitin ligases (CRLs) that are highly diverse and play a role in myriad cellular processes, most notably protein degradation by ubiquitination.

<span class="mw-page-title-main">COP9 signalosome</span>

COP9 signalosome (CSN) is a protein complex with isopeptidase activity. It catalyses the hydrolysis of NEDD8 protein from the cullin subunit of Cullin-RING ubiquitin ligases (CRL). Therefore, it is responsible for CRL deneddylation – at the same time, it is able to bind denedyllated cullin-RING complex and retain them in deactivated form. COP9 signalosome thus serves as a sole deactivator of CRLs. The complex was originally identified in plants, and subsequently found in all eukaryotic organisms including human. Human COP9 signalosome consists of 8 subunits - CSN1, CSN2, CSN3, CSN4, CSN5, CSN6, CSN7, CSN8. All are essential for full function of the complex and mutation in some of them is lethal in mice.

Raymond Joseph Deshaies is an American biochemist and cell biologist. He is senior vice president of global research at Amgen and a visiting associate at the California Institute of Technology (Caltech). Prior to that, he was a professor of biology at Caltech and an investigator of the Howard Hughes Medical Institute. He is also the co-founder of the biotechnology companies Proteolix and Cleave Biosciences. His research focuses on mechanisms and regulation of protein homeostasis in eukaryotic cells, with a particular focus on how proteins are conjugated with ubiquitin and degraded by the proteasome.

<span class="mw-page-title-main">Nicolas H. Thomä</span> German structural and chemical biologist

Nicolas H. Thomä is a German researcher, full professor at the EPFL School of Life Sciences and Director of the Paternot Chair for Cancer Research in Lausanne, Switzerland. He is a biochemist and structural biologist and a leading researcher in the fields of ubiquitin ligase biology and DNA repair.

Ning Zheng is an experimental structural biologist and protein biochemist known for his pioneering work in the fields of molecular glues and targeted protein degradation. He is currently a professor in the Department of Pharmacology at the University of Washington School of Medicine and a Howard Hughes Medical Institute (HHMI) Investigator.

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References

  1. ↑ Cardozo, Timothy; Pagano, Michele (September 2004). "The SCF ubiquitin ligase: insights into a molecular machine". Nature Reviews. Molecular Cell Biology. 5 (9): 739–751. doi:10.1038/nrm1471. ISSN   1471-0072. PMID   15340381. S2CID   11118665.
  2. ↑ Petroski, Matthew D.; Deshaies, Raymond J. (January 2005). "Function and regulation of cullin-RING ubiquitin ligases". Nature Reviews. Molecular Cell Biology. 6 (1): 9–20. doi:10.1038/nrm1547. ISSN   1471-0072. PMID   15688063. S2CID   24159190.
  3. ↑ Skaar, Jeffrey R.; Pagan, Julia K.; Pagano, Michele (June 2013). "Mechanisms and function of substrate recruitment by F-box proteins". Nature Reviews. Molecular Cell Biology. 14 (6): 369–381. doi:10.1038/nrm3582. ISSN   1471-0080. PMC   3827686 . PMID   23657496.
  4. ↑ Frescas, David; Pagano, Michele (June 2008). "Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer". Nature Reviews. Cancer. 8 (6): 438–449. doi:10.1038/nrc2396. ISSN   1474-1768. PMC   2711846 . PMID   18500245.
  5. ↑ Wang, Zhiwei; Liu, Pengda; Inuzuka, Hiroyuki; Wei, Wenyi (April 2014). "Roles of F-box proteins in cancer". Nature Reviews. Cancer. 14 (4): 233–247. doi:10.1038/nrc3700. ISSN   1474-1768. PMC   4306233 . PMID   24658274.
  6. ↑ Skaar, Jeffrey R.; Pagan, Julia K.; Pagano, Michele (December 2014). "SCF ubiquitin ligase-targeted therapies". Nature Reviews. Drug Discovery. 13 (12): 889–903. doi:10.1038/nrd4432. ISSN   1474-1784. PMC   4410837 . PMID   25394868.
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