Try a new search

Format these results:

Searched for:

person:paganm02

in-biosketch:yes

Total Results:

256


Stabilization of GTSE1 by cyclin D1-CDK4/6 promotes cell proliferation: relevance in cancer prognosis

García-Vázquez, Nelson; González-Robles, Tania J; Lane, Ethan; Spasskaya, Daria; Zhang, Qingyue; Kerzhnerman, Marc; Jeong, YeonTae; Collu, Marta; Simoneschi, Daniele; Ruggles, Kelly V; Rona, Gergely; Pagano, Michele; Kaisari, Sharon
Cyclin D1 is the activating subunit of the cell cycle kinases CDK4 and CDK6, and its dysregulation is a well-known oncogenic driver in many human cancers. The biological function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G2 and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unknown substrate of cyclin D1-CDK4/6. The phosphorylation of GTSE1 mediated by cyclin D1-CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 also during the G1 phase of the cell cycle. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1's role in cell cycle control and oncogenesis beyond RB phosphorylation.
PMCID:11230433
PMID: 38979260
ISSN: 2692-8205
CID: 5732262

The FBXO45-GEF-H1 axis controls germinal center formation and B-cell lymphomagenesis

Sahasrabuddhe, Anagh A; Chen, Xiaofei; Ma, Kaiyu; Wu, Rui; Liang, Huan-Chang; Kapoor, Richa; Chhipa, Rishi R; Onder, Ozlem; McFetridge, Courtney; Van Arnam, John S; Zhang, Xiao; Morrissette, Jennifer J D; Pillai, Vinodh; Li, Marilyn M; Szankasi, Philippe; Basrur, Venkatesha; Conlon, Kevin P; Raabe, Tobias D; Bailey, Nathanael G; Hogaboam, Cory M; Rottapel, Robert; Kim, Junhyong; López, Cristina; Schlesner, Matthias; Siebert, Reiner; Dreval, Kostiantyn; Morin, Ryan D; Moro, Loredana; Pagano, Michele; Staudt, Louis M; Lim, Megan S; Elenitoba-Johnson, Kojo S J
The role of ubiquitin-mediated degradation mechanisms in the pathogenesis of diffuse large B cell (DLBCL) and follicular lymphoma (FL) is not completely understood. We show that conditional deletion of the E3 ubiquitin ligase Fbxo45 in germinal center B-cells results in B-cell lymphomagenesis in homozygous (100%) and heterozygous (48%) mice. Mechanistically, FBXO45 targets the RHO guanine exchange factor ARHGEF2/GEF-H1 for ubiquitin-mediated degradation. Double genetic ablation of Fbxo45 and Arhgef2 ameliorated lymphoma formation. Transgenic knock-in mice harboring a GEF-H1 mutant unable to bind FBXO45 develop B-cell lymphomas with ~50% penetrance. Genome sequencing in human lymphomas identified mutually-exclusive FBXO45 copy number losses and ARHGEF2 gains, with combined frequencies ranging from 26.32% in FL to 45.12% in DLBCL. Notably, FBXO45 silencing enhances sensitivity to MEK1/2 inhibition. These results identify FBXO45 and ARHGEF2 as a novel tumor-suppressor and oncogene pair involved in the pathogenesis of B-cell lymphomas with significant implications for targeted therapies.
PMID: 39820335
ISSN: 2159-8290
CID: 5777282

The FBXO45-GEF-H1 axis controls germinal center formation and B-cell lymphomagenesis

Sahasrabuddhe, Anagh A; Chen, Xiaofei; Ma, Kaiyu; Wu, Rui; Liang, Huan-Chang; Kapoor, Richa; Chhipa, Rishi R; Onder, Ozlem; McFetridge, Courtney; Van Arnam, John S; Zhang, Xiao; Morrissette, Jennifer J D; Pillai, Vinodh; Li, Marilyn M; Szankasi, Philippe; Basrur, Venkatesha; Conlon, Kevin P; Raabe, Tobias D; Bailey, Nathanael G; Hogaboam, Cory M; Rottapel, Robert; Kim, Junhyong; López, Cristina; Schlesner, Matthias; Siebert, Reiner; Dreval, Kostiantyn; Morin, Ryan D; Moro, Loredana; Pagano, Michele; Staudt, Louis M; Lim, Megan S; Elenitoba-Johnson, Kojo S J
The role of ubiquitin-mediated degradation mechanisms in the pathogenesis of diffuse large B cell (DLBCL) and follicular lymphoma (FL) is not completely understood. We show that conditional deletion of the E3 ubiquitin ligase Fbxo45 in germinal center B-cells results in B-cell lymphomagenesis in homozygous (100%) and heterozygous (48%) mice. Mechanistically, FBXO45 targets the RHO guanine exchange factor ARHGEF2/GEF-H1 for ubiquitin-mediated degradation. Double genetic ablation of Fbxo45 and Arhgef2 ameliorated lymphoma formation. Transgenic knock-in mice harboring a GEF-H1 mutant unable to bind FBXO45 develop B-cell lymphomas with ~50% penetrance. Genome sequencing in human lymphomas identified mutually-exclusive FBXO45 copy number losses and ARHGEF2 gains, with combined frequencies ranging from 26.32% in FL to 45.12% in DLBCL. Notably, FBXO45 silencing enhances sensitivity to MEK1/2 inhibition. These results identify FBXO45 and ARHGEF2 as a novel tumor-suppressor and oncogene pair involved in the pathogenesis of B-cell lymphomas with significant implications for targeted therapies.
PMID: 39820335
ISSN: 2159-8290
CID: 5777272

Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress

Cao, Shiyun; Garcia, Sheena Faye; Shi, Huigang; James, Ellie I; Kito, Yuki; Shi, Hui; Mao, Haibin; Kaisari, Sharon; Rona, Gergely; Deng, Sophia; Goldberg, Hailey V; Ponce, Jackeline; Ueberheide, Beatrix; Lignitto, Luca; Guttman, Miklos; Pagano, Michele; Zheng, Ning
Ubiquitin-dependent proteolysis regulates diverse cellular functions with high substrate specificity, which hinges on the ability of ubiquitin E3 ligases to decode the targets' degradation signals, i.e., degrons. Here, we show that BACH1, a transcription repressor of antioxidant response genes, features two distinct unconventional degrons encrypted in the quaternary structure of its homodimeric BTB domain. These two degrons are both functionalized by oxidative stress and are deciphered by two complementary E3s. FBXO22 recognizes a degron constructed by the BACH1 BTB domain dimer interface, which is unmasked from transcriptional co-repressors after oxidative stress releases BACH1 from chromatin. When this degron is impaired by oxidation, a second BACH1 degron manifested by its destabilized BTB dimer is probed by a pair of FBXL17 proteins that remodels the substrate into E3-bound monomers for ubiquitination. Our findings highlight the multidimensionality of protein degradation signals and the functional complementarity of different ubiquitin ligases targeting the same substrate.
PMID: 39504958
ISSN: 1097-4172
CID: 5766842

FBXO38 is dispensable for PD-1 regulation

Dibus, Nikol; Salyova, Eva; Kolarova, Karolina; Abdirov, Alikhan; Pagano, Michele; Stepanek, Ondrej; Cermak, Lukas
SKP1-CUL1-F-box protein (SCF) ubiquitin ligases are versatile protein complexes that mediate the ubiquitination of protein substrates. The direct substrate recognition relies on a large family of F-box-domain-containing subunits. One of these substrate receptors is FBXO38, which is encoded by a gene found mutated in families with early-onset distal motor neuronopathy. SCFFBXO38 ubiquitin ligase controls the stability of ZXDB, a nuclear factor associated with the centromeric chromatin protein CENP-B. Loss of FBXO38 in mice results in growth retardation and defects in spermatogenesis characterized by deregulation of the Sertoli cell transcription program and compromised centromere integrity. Moreover, it was reported that SCFFBXO38 mediates the degradation of PD-1, a key immune-checkpoint inhibitor in T cells. Here, we have re-addressed the link between SCFFBXO38 and PD-1 proteolysis. Our data do not support the notion that SCFFBXO38 directly or indirectly controls the abundance and stability of PD-1 in T cells.
PMID: 39266770
ISSN: 1469-3178
CID: 5690692

Identification of a novel alternative splicing isoform of the Hippo kinase STK3/MST2 with impaired kinase and cell growth suppressing activities

Rodrigues, Ana Maria; Paula Zen Petisco Fiore, Ana; Guardia, Gabriela D A; Tomasin, Rebeka; Azevedo Reis Teixeira, André; Giordano, Ricardo Jose; Schechtman, Deborah; Pagano, Michele; Galante, Pedro A F; Bruni-Cardoso, Alexandre
Mammalian Ste-20-like Kinases 1 and 2 (MST1/2) are core serine-threonine kinases of the Hippo pathway regulating several cellular processes, including cell cycle arrest and cell death. Here, we discovered a novel alternative splicing variant of the MST2 encoding gene, STK3, in malignant cells and tumor datasets. This variant, named STK3∆7 or MST2∆7 (for mRNA or protein, respectively), resulted from the skipping of exon 7. MST2∆7 exhibited increased ubiquitylation and interaction with the E3 ubiquitin-protein ligase CHIP compared to the full-length protein (MST2FL). Exon 7 in STK3 encodes a segment within the kinase domain, and its exclusion compromised MST2 interaction with and phosphorylation of MOB, a major MST1/2 substrate. Nevertheless, MST2∆7 was capable of interacting with MST1 and MST2FL. Unlike MST2FL, overexpression of MST2∆7 did not lead to increased cell death and growth arrest. Strikingly, we observed the exclusion of STK3 exon 7 in 3.2-15% of tumor samples from patients of several types of cancer, while STK3∆7 was seldomly found in healthy tissues. Our study identified a novel STK3 splicing variant with loss of function and the potential to disturb tissue homeostasis by impacting on MST2 activities in the regulation of cell death and quiescence.
PMID: 39174858
ISSN: 1476-5594
CID: 5681082

PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4

Nguyen-Dien, Giang Thanh; Townsend, Brendan; Kulkarni, Prajakta Gosavi; Kozul, Keri-Lyn; Ooi, Soo Siang; Eldershaw, Denaye N; Weeratunga, Saroja; Liu, Meihan; Jones, Mathew Jk; Millard, S Sean; Ng, Dominic Ch; Pagano, Michele; Bonfim-Melo, Alexis; Schneider, Tobias; Komander, David; Lazarou, Michael; Collins, Brett M; Pagan, Julia K
Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.
PMCID:11316107
PMID: 38992176
ISSN: 1469-3178
CID: 5701782

CDK-independent role of D-type cyclins in regulating DNA mismatch repair

Rona, Gergely; Miwatani-Minter, Bearach; Zhang, Qingyue; Goldberg, Hailey V; Kerzhnerman, Marc A; Howard, Jesse B; Simoneschi, Daniele; Lane, Ethan; Hobbs, John W; Sassani, Elizabeth; Wang, Andrew A; Keegan, Sarah; Laverty, Daniel J; Piett, Cortt G; Pongor, Lorinc S; Xu, Miranda Li; Andrade, Joshua; Thomas, Anish; Sicinski, Piotr; Askenazi, Manor; Ueberheide, Beatrix; Fenyö, David; Nagel, Zachary D; Pagano, Michele
Although mismatch repair (MMR) is essential for correcting DNA replication errors, it can also recognize other lesions, such as oxidized bases. In G0 and G1, MMR is kept in check through unknown mechanisms as it is error-prone during these cell cycle phases. We show that in mammalian cells, D-type cyclins are recruited to sites of oxidative DNA damage in a PCNA- and p21-dependent manner. D-type cyclins inhibit the proteasomal degradation of p21, which competes with MMR proteins for binding to PCNA, thereby inhibiting MMR. The ability of D-type cyclins to limit MMR is CDK4- and CDK6-independent and is conserved in G0 and G1. At the G1/S transition, the timely, cullin-RING ubiquitin ligase (CRL)-dependent degradation of D-type cyclins and p21 enables MMR activity to efficiently repair DNA replication errors. Persistent expression of D-type cyclins during S-phase inhibits the binding of MMR proteins to PCNA, increases the mutational burden, and promotes microsatellite instability.
PMID: 38458201
ISSN: 1097-4164
CID: 5655612

The REEP5/TRAM1 complex binds SARS-CoV-2 NSP3 and promotes virus replication

Li, Jie; Gui, Qi; Liang, Feng-Xia; Sall, Joseph; Zhang, Qingyue; Duan, Yatong; Dhabaria, Avantika; Askenazi, Manor; Ueberheide, Beatrix; Stapleford, Kenneth A; Pagano, Michele
Generation of virus-host protein-protein interactions (PPIs) maps may provide clues to uncover SARS-CoV-2-hijacked cellular processes. However, these PPIs maps were created by expressing each viral protein singularly, which does not reflect the life situation in which certain viral proteins synergistically interact with host proteins. Our results reveal the host-viral protein-protein interactome of SARS-CoV-2 NSP3, NSP4, and NSP6 expressed individually or in combination. Furthermore, REEP5/TRAM1 complex interacts with NSP3 at ROs and promotes viral replication. The significance of our research is identifying virus-host interactions that may be targeted for therapeutic intervention.
PMCID:10617467
PMID: 37768083
ISSN: 1098-5514
CID: 5614142

A noncanonical function of SKP1 regulates the switch between autophagy and unconventional secretion

Li, Jie; Krause, Gregory J; Gui, Qi; Kaushik, Susmita; Rona, Gergely; Zhang, Qingyue; Liang, Feng-Xia; Dhabaria, Avantika; Anerillas, Carlos; Martindale, Jennifer L; Vasilyev, Nikita; Askenazi, Manor; Ueberheide, Beatrix; Nudler, Evgeny; Gorospe, Myriam; Cuervo, Ana Maria; Pagano, Michele
Intracellular degradation of proteins and organelles by the autophagy-lysosome system is essential for cellular quality control and energy homeostasis. Besides degradation, endolysosomal organelles can fuse with the plasma membrane and contribute to unconventional secretion. Here, we identify a function for mammalian SKP1 in endolysosomes that is independent of its established role as an essential component of the family of SCF/CRL1 ubiquitin ligases. We found that, under nutrient-poor conditions, SKP1 is phosphorylated on Thr131, allowing its interaction with V1 subunits of the vacuolar ATPase (V-ATPase). This event, in turn, promotes V-ATPase assembly to acidify late endosomes and enhance endolysosomal degradation. Under nutrient-rich conditions, SUMOylation of phosphorylated SKP1 allows its binding to and dephosphorylation by the PPM1B phosphatase. Dephosphorylated SKP1 interacts with SEC22B to promote unconventional secretion of the content of less acidified hybrid endosomal/autophagic compartments. Collectively, our study implicates SKP1 phosphorylation as a switch between autophagy and unconventional secretion in a manner dependent on cellular nutrient status.
PMCID:10575587
PMID: 37831778
ISSN: 2375-2548
CID: 5604232