Matrix metalloproteinase‐2 mediates ribosomal RNA transcription by cleaving nucleolar histones

Ali, Mohammad; García-Vilas, Javier A.; Cromwell, Christopher R; Hubbard, Basil P.; Hendzel, Michael J.; Schulz, Richard

doi:10.1111/febs.16061

Cited by 18 publications

(33 citation statements)

References 56 publications

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“…During cerebral ischemia, MMP-2 targets DNA repair proteins poly ADP ribose polymerase (PARP)-1, X-ray repair cross complementing protein-1, and 8-oxoguanine DNA glycosylase-1 and decreases their activity in rat cortical neurons during I/R injury [131]. Our group recently detected MMP-2 inside the nucleolus of osteosarcoma cell lines where it promotes ribosomal RNA transcription and cell proliferation via, at least in part, cleavage of the N-terminal tail of histone H3 [132]. MMP-9 is also reported to be localized to the nucleus and regulate gene expression through selective proteolysis of the histone H3 tail during osteoclastogenesis [133].…”

Section: Nucleus/nucleolusmentioning

confidence: 99%

Multifunctional intracellular matrix metalloproteinases: implications in disease

2021

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Matrix metalloproteinases (MMPs) are zinc‐dependent endopeptidases that were first discovered as proteases, which target and cleave extracellular proteins. During the past 20 years, however, intracellular roles of MMPs were uncovered and research on this new aspect of their biology expanded. MMP‐2 is the first of this protease family to be reported to play a crucial intracellular role where it cleaves several sarcomeric proteins inside cardiac myocytes during oxidative stress‐induced injury. Beyond MMP‐2, currently at least eleven other MMPs are known to function intracellularly including MMP‐1, MMP‐3, MMP‐7, MMP‐8, MMP‐9, MMP‐10, MMP‐11, MMP‐12, MMP‐14, MMP‐23 and MMP‐26. These intracellular MMPs are localized to different compartments inside the cell including the cytosol, sarcomere, mitochondria, and the nucleus. Intracellular MMPs contribute to the pathogenesis of various diseases. Cardiovascular renal disorders, inflammation, and malignancy are some examples. They also exert antiviral and bactericidal effects. Interestingly, MMPs can act intracellularly through both protease‐dependent and protease‐independent mechanisms. In this review, we will highlight the intracellular mechanisms of MMPs activation, their numerous subcellular locales, substrates, and roles in different pathological conditions. We will also discuss the future direction of MMP research and the necessity to exploit the knowledge of their intracellular targets and actions for the design of targeted inhibitors.

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Section: Nucleus/nucleolusmentioning

confidence: 99%

Multifunctional intracellular matrix metalloproteinases: implications in disease

2021

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“…Similarly, tumstatin, which is a 28 kDa matrikine released by MMP9 from the α3-chain of type IV collagen (COL4α3), was found to suppress cancer growth through αvβ3 integrin-mediated antiangiogenic activity. It was observed that MMP9-deficient mice were characterized by decreased levels of circulating tumstatin linked to an increased rate of tumor growth, and this effect was reversed upon restoration of the physiological concentration of tumstatin in blood [ 154 ]. Additionally, MMP9 was reported to have a tumor suppressor role in colitis-associated cancers (CACs) by the activation of Notch1-dependent intracellular signal transmitters that triggered cell apoptosis, cell-cycle arrest, and DNA damage [ 155 , 156 ].…”

Section: Mmp9 and Cancermentioning

confidence: 99%

MMP9: A Tough Target for Targeted Therapy for Cancer

Augoff

Hryniewicz-Jankowska

Taboła

et al. 2022

Cancers

123

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Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs.

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“…The localization of MMP-2 to the promotor region of the ribosomal DNA genes in the nucleolus suggests it regulates ribosomal RNA transcription [6]. Indeed inhibition of MMP-2 genetically or pharmacologically was associated with reduced both pre-ribosomal RNA transcription and cell proliferation [87]. We also found that nucleolar MMP-2 activity regulates RNA transcription through the clipping of histone H3, as H3 cleavage is associated with increased ribosomal RNA transcription and minimal or absence of H3 cleavage, when MMP-2 is inhibited, results in reduction in transcription, as well as cell proliferation [87].…”

Section: Novel Roles Of Mmp-2 Inside Cellsmentioning

confidence: 99%

“…Indeed inhibition of MMP-2 genetically or pharmacologically was associated with reduced both pre-ribosomal RNA transcription and cell proliferation [87]. We also found that nucleolar MMP-2 activity regulates RNA transcription through the clipping of histone H3, as H3 cleavage is associated with increased ribosomal RNA transcription and minimal or absence of H3 cleavage, when MMP-2 is inhibited, results in reduction in transcription, as well as cell proliferation [87]. Another study also found that MMP-9 (Gelatinase-B, closely related to MMP-2) is able to clip histone H3 and regulates genes expression involved in melanoma formation [88].…”

Section: Novel Roles Of Mmp-2 Inside Cellsmentioning

confidence: 99%

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu

Maybee¹,

Ink²,

Ali³

2022

Preprint

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Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at the respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two MMPs closely related: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and genes expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus, and functions in calcium regulation, contractile dysfunction, genes expression and ribosomal RNA transcription. Our particular interest lies in the role MMP-2 and MT1-MMP serve within the nucleus, as it may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies in cancer and other diseases.

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Matrix metalloproteinase‐2 mediates ribosomal RNA transcription by cleaving nucleolar histones

Cited by 18 publications

References 56 publications

Multifunctional intracellular matrix metalloproteinases: implications in disease

Multifunctional intracellular matrix metalloproteinases: implications in disease

MMP9: A Tough Target for Targeted Therapy for Cancer

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu

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