Differential Regulation of Cellular Senescence and Differentiation by Prolyl Isomerase Pin1 in Cardiac Progenitor Cells

Toko, Haruhiro; Hariharan, Nirmala; Konstandin, Mathias; Ormachea, Lucia; McGregor, Michael; Gude, Natalie; Sundararaman, Balaji; Joyo, Eri; Joyo, Anya; Din, Shabana; Mohsin, Sadia; Uchida, Takafumi; Sussman, Mark A.

doi:10.1074/jbc.m113.526442

Cited by 29 publications

(35 citation statements)

References 50 publications

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“…By stabilizing Nanog, β-catenin and Notch, Pin1 extends its influences on stem cell differentiation and commitment (8, 39). Corroborating findings in other stem cells, our recent study demonstrates Pin1 as a pivotal regulator of stem cell maintenance in adult c-kit+ CPCs (4). …”

Section: Pin1 In Cardiac Progenitor Cells: Determining Cell Fatesupporting

confidence: 77%

“…Over the past couple of years, our lab has been actively studying the impact of Pin1 signaling in the heart and characterizing a cell specific role in cardiac myocytes and c-kit+ cardiac progenitor cells (CPCs) (1, 4). Pin1is highly expressed and mainly localized to the nucleus in the neonatal heart; transition into adulthood is associated with a reduction in expression and switch to cytosolic localization in the myocardium (1).…”

Section: Pin1 and Cardiac Hypertrophy: Choosing Between Signalsmentioning

confidence: 99%

“…Endogenous Pin1 expression correlates with the proliferative potential of CPCs, with decline in Pin1 levels observed under growth arrest conditions such as serum starvation and Dexamethasone-induced differentiation (4). A tight control of Pin1 expression is apparently critical for cellular growth and proliferation, as dysregulation of Pin1 via either loss or gain of function approaches causes cell cycle arrest at the G1/S and G2/M phases respectively in CPCs (4).…”

Section: Pin1 In Cardiac Progenitor Cells: Determining Cell Fatementioning

confidence: 99%

“…A tight control of Pin1 expression is apparently critical for cellular growth and proliferation, as dysregulation of Pin1 via either loss or gain of function approaches causes cell cycle arrest at the G1/S and G2/M phases respectively in CPCs (4). Consistently, Pin1KO mice have fewer cycling CPCs positive for cell cycle marker Ki-67 by 1 week after myocardial infarction.…”

Section: Pin1 In Cardiac Progenitor Cells: Determining Cell Fatementioning

confidence: 99%

“…The regulatory role of Pin1 in signaling has received increasing attention in the cancer field but remains relatively unexplored in the context of cardiac biology. This review discusses the significance of Pin1 that functions as a “molecular timer” to fine tune the signal amplitude and duration of a myriad of cardiovascular signaling networks (1, 3, 4). …”

Section: Introduction: a Place For Pin1 In The Molecular Circuitry Ofmentioning

confidence: 99%

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Pin1: A molecular orchestrator in the heart

Hariharan

Sussman

2014

Trends in Cardiovascular Medicine

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Pin1 is an evolutionarily conserved peptidyl-prolyl isomerase that binds and changes the three dimensional conformation of specific phospho-proteins. By regulating protein structure and folding, Pin1 affects the stability, interaction and activity of a broad spectrum of target proteins thus impacting upon diverse cellular processes. This review discusses the pivotal role Pin1 plays in regulating cardiac pathophysiology by functioning as a “molecular orchestrator” of a myriad of signal transduction pathways in the heart.

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Section: Pin1 In Cardiac Progenitor Cells: Determining Cell Fatesupporting

confidence: 77%

Section: Pin1 and Cardiac Hypertrophy: Choosing Between Signalsmentioning

confidence: 99%

Section: Pin1 In Cardiac Progenitor Cells: Determining Cell Fatementioning

confidence: 99%

Section: Pin1 In Cardiac Progenitor Cells: Determining Cell Fatementioning

confidence: 99%

Section: Introduction: a Place For Pin1 In The Molecular Circuitry Ofmentioning

confidence: 99%

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Pin1: A molecular orchestrator in the heart

Hariharan

Sussman

2014

Trends in Cardiovascular Medicine

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Beyond cardiomyocyte loss: Role of Notch in cardiac aging

Rizzo

Bertero

Ferrari

et al. 2018

Journal Cellular Physiology

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The knowledge of the cellular events occurring in the aging heart has dramatically expanded in the last decade and is expected to further grow in years to come. It is now clear that impaired function and loss of cardiomyocytes are major features of cardiac aging, but other events are likewise important. In particular, accumulating experimental evidence highlights the importance of fibroblast and cardiac progenitor cell (CPC) dysfunction. The Notch pathway regulates cardiomyocyte, fibroblast, and CPC activity and, thus, may be critically involved in heart disease associated with advanced age, especially heart failure. In a translational perspective, thorough investigation of the Notch system in the aging myocardium may lead to the identification of molecular targets for novel therapies for age-related cardiac disease.

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Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation

et al. 2015

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Autologous transplantation of cardiac progenitor cells (CPCs) alleviates myocardial dysfunction in the damaged heart; however, the mechanisms that contribute to their reparative qualities remain poorly understood. In this study, we examined CPC metabolism to elucidate the metabolic pathways that regulate their proliferative capacity. In complete growth medium, undifferentiated CPCs isolated from adult mouse heart proliferated rapidly (Td = 13.8 h). CPCs expressed the Glut1 transporter and their glycolytic rate was increased by high extracellular glucose concentration, in the absence of insulin. Although high glucose concentrations did not stimulate proliferation, glutamine increased CPC doubling time and promoted survival under conditions of oxidative stress. In comparison with glucose, pyruvate or BSA-palmitate, glutamine, when provided as the sole metabolic substrate, increased ATP-linked and uncoupled respiration. Although fatty acids were not used as respiratory substrates when present as a sole carbon source, glutamine-induced respiration was doubled in the presence of BSA-palmitate, suggesting that glutamine stimulates fatty acid oxidation. Additionally, glutamine promoted rapid phosphorylation of the mTORC1 substrate, p70S6k, as well as retinoblastoma protein, followed by induction of cyclin D1 and cdk4. Inhibition of either mTORC1 or glutaminolysis was sufficient to diminish CPC proliferation, and provision of cell permeable α-ketoglutarate in the absence of glutamine increased both respiration and cell proliferation, indicating a key role of glutamine anaplerosis in cell growth. These findings suggest that glutamine, by enhancing mitochondrial function and stimulating mTORC1, increases CPC proliferation, and that interventions to increase glutamine uptake or oxidation may improve CPC therapy.

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Differential Regulation of Cellular Senescence and Differentiation by Prolyl Isomerase Pin1 in Cardiac Progenitor Cells

Cited by 29 publications

References 50 publications

Pin1: A molecular orchestrator in the heart

Pin1: A molecular orchestrator in the heart

Beyond cardiomyocyte loss: Role of Notch in cardiac aging

Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation

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