p21<sup>Waf1/Cip1</sup>REGULATES PROLIFERATION AND APOPTOSIS IN AIRWAY EPITHELIAL CELLS AND ALTERNATIVE FORMS HAVE ALTERED BINDING ACTIVITIES

Blundell, Renald; Harrison, David J.; O’Dea, Shirley

doi:10.1080/01902140490476373

Cited by 14 publications

(13 citation statements)

References 39 publications

(48 reference statements)

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“…While Akt activation promotes nuclear export of p21, an alternate trafficking possibility is Brap2 retention of p21 in the cytoplasm and prevention of nuclear import (31). Also, a truncated form of p21 at the NLS-containing carboxy-terminus was identified in primary alveolar epithelial cell cultures treated with hyperoxia (32). It is not known if p21 truncation was due to a cleavage event or involves alternate p21 transcripts (33).…”

Section: Discussionmentioning

confidence: 99%

p21Cip1 protects against oxidative stress by suppressing ER-dependent activation of mitochondrial death pathways

Vitiello

Staversky

et al. 2009

Free Radical Biology and Medicine

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Although it is well established that the cell cycle inhibitor p21 protects against genotoxic stress by preventing the replication of damaged DNA, recent studies have shown cytoplasmic forms can also protect. It protects by delaying the loss of the anti-apoptotic proteins, Mcl-1 and Bcl-XL; however, the mechanism of regulation is unknown. Utilizing hyperoxia as a model of chronic oxidative stress and DNA damage, p21 was detected in the nucleus and cytoplasm and cytoplasmic expression of p21 was sufficient for cytoprotection. P21 was enriched in a subcellular fraction containing mitochondria and endoplasmic reticulum (ER), suggesting that it may be coordinating ER and mitochondrial stress pathways. Consistent with this, p21 suppressed hyperoxic downregulation of BiP and subsequent activation ER stress signaling which effected Mcl-1, but not Bcl-XL; though both inhibited hyperoxic cell death. Taken together, these data show that p21 integrates the DNA damage response with ER stress signaling which then regulates mitochondrial death pathways during chronic genotoxic stress.

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Section: Discussionmentioning

confidence: 99%

p21Cip1 protects against oxidative stress by suppressing ER-dependent activation of mitochondrial death pathways

Vitiello

Staversky

et al. 2009

Free Radical Biology and Medicine

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“…In addition to negative regulation of branching morphogenesis in the embryonic lung, TGF-β/Smad signaling and expression of cyclin-dependent kinase inhibitors blocks proliferation of mature alveolar type II cells in culture [24]–[28]. Further, alveolar epithelial cells from p21 −/− mice have an increased proliferation rate and lung tumorigenesis is enhanced in adult mice heterozygous for a null mutation in TGF-β1 , supporting a role for this pathway in maintaining quiescence in the normal respiratory epithelium in vivo [29]–[31]. Whether TGF-β/Smad signaling and cyclin-dependent kinase inhibitors contribute to negative regulation of progenitor cell activation and cell cycle reentry in the mature respiratory epithelium has not been determined.…”

Section: Introductionmentioning

confidence: 87%

Sox17 Promotes Cell Cycle Progression and Inhibits TGF-β/Smad3 Signaling to Initiate Progenitor Cell Behavior in the Respiratory Epithelium

et al. 2009

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The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-β)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-β1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells.

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“…p21 deletion accelerates the proliferation of a variety of normal cell types, including neuroblasts, forebrain stem cells, HSCs, hepatocytes, airway epithelial cells, and Sertoli cells (Blundell et al, 2004; Cheng et al, 2000; Holsberger et al, 2005; Kippin et al, 2005; Pechnick et al, 2008; Sheahan et al, 2007). However, although hematopoietic stem cells from p21-deficient mice are more mitotically active than HSCs from p21+/+ mice under normal homeostatic conditions, they fail to proliferate following exposure to cell cycle-specific myelotoxic injury and are less able to repopulate the hematopoietic system of irradiated recipient mice (Cheng et al, 2000).…”

Section: Effectors Of P53 Tumor Suppressionmentioning

confidence: 99%

Antagonistic pleiotropy and p53

Ungewitter

Scrable

2009

Mechanisms of Ageing and Development

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p21^Waf1/Cip1REGULATES PROLIFERATION AND APOPTOSIS IN AIRWAY EPITHELIAL CELLS AND ALTERNATIVE FORMS HAVE ALTERED BINDING ACTIVITIES

Cited by 14 publications

References 39 publications

p21Cip1 protects against oxidative stress by suppressing ER-dependent activation of mitochondrial death pathways

p21Cip1 protects against oxidative stress by suppressing ER-dependent activation of mitochondrial death pathways

Sox17 Promotes Cell Cycle Progression and Inhibits TGF-β/Smad3 Signaling to Initiate Progenitor Cell Behavior in the Respiratory Epithelium

Antagonistic pleiotropy and p53

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p21Waf1/Cip1REGULATES PROLIFERATION AND APOPTOSIS IN AIRWAY EPITHELIAL CELLS AND ALTERNATIVE FORMS HAVE ALTERED BINDING ACTIVITIES

Cited by 14 publications

References 39 publications

p21Cip1 protects against oxidative stress by suppressing ER-dependent activation of mitochondrial death pathways

p21Cip1 protects against oxidative stress by suppressing ER-dependent activation of mitochondrial death pathways

Sox17 Promotes Cell Cycle Progression and Inhibits TGF-β/Smad3 Signaling to Initiate Progenitor Cell Behavior in the Respiratory Epithelium

Antagonistic pleiotropy and p53

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p21^Waf1/Cip1REGULATES PROLIFERATION AND APOPTOSIS IN AIRWAY EPITHELIAL CELLS AND ALTERNATIVE FORMS HAVE ALTERED BINDING ACTIVITIES