Antiproliferative Autoantigen CDA1 Transcriptionally Up-regulates p21Waf1/Cip1 by Activating p53 and MEK/ERK1/2 MAPK Pathways

Tu, Yugang; Wu, Weiping; Wu, Tieqiao; Cao, Zemin; Wilkins, Richard J.; Toh, Ban Hock; Cooper, Mark E.; Chai, Zhonglin

doi:10.1074/jbc.m609623200

Cited by 60 publications

(81 citation statements)

References 65 publications

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“…The character of a resulting cellular response is partially regulated by the intensity and kinetics of MAPK signaling. For example, sustained strong activation of the ERK 1/2 pathway induces cell cycle arrest in intestinal epithelial and HeLa cells, leading to transcriptional down-regulation of cyclin D1 and up-regulation of p21 and p27 (23,31). Prolonged ERK 1/2 activation is also associated with either senescence or apoptosis in fibroblasts and differentiation in neurons and PC12 cells (61).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it was recently reported that sustained, strong activation of the ERK 1/2 pathway induces cell cycle arrest in intestinal epithelial and HeLa cells, leading to transcriptional down-regulation of cyclin D1 and up-regulation of p21 and p27 (23,31). Thus, the selective enhancement of ERK 1/2 phosphorylation by TGF-␤ priming suggests that this biochemical event may directly regulate p21 or cyclin D1 expression in T cells a Control and PBT treated with TGF-␤ for 72 h were activated by plate-bound OKT3 and soluble anti-CD28 for the final 48 h as described for proliferation in Fig.…”

Section: Prolonged Tcr Signaling Corresponds With Increased Expressiomentioning

confidence: 99%

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TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

Das¹,

Levine

2008

The Journal of Immunology

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TGF-β signaling is critical for controlling naive T cell homeostasis and differentiation; however, the biological and biochemical changes induced by TGF-β in effector/memory T cells are poorly defined. We show that although TGF-β inhibits effector/memory peripheral blood T lymphoblast proliferation and IL-2 production, the intensity and kinetics for TCR-induced global tyrosine phosphorylation are markedly increased compared with that in untreated cells or naive T cells. After TCR ligation, tyrosine phosphorylation of proximal tyrosine kinases and docking proteins like linker for activation of T cells is maintained for >30 min in TGF-β-primed cells compared with untreated cells where phosphorylation of these targets returned to basal levels by 10 min. Extended phosphorylation of linker for activation of T cells in treated peripheral blood T selectively prolongs ERK 1/2 signaling and phospholipase C-γ1 activation leading to increased Ca2+ flux. A kinase/phosphatase imbalance could not account for extended phosphorylation as CD45R, SHP-1, and SHP-2 expression remains unaltered. The contradiction between prolonged signal transduction and inhibition of proliferation is partially explained by the observation that TGF-β priming results in ERK 1/2-independent p21 induction and decreased cyclin D1 expression leading to accumulation of T cells in G0/G1 phases of the cell cycle and cell cycle arrest. Despite inhibition of T cell function by TGF-β priming, TCR and cytokine signaling pathways are intact and selectively extended, suggesting that suppression in the effector/memory T cell is mediated by reprogramming signal transduction, rather than its inhibition as in the naive T cell.

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Section: Discussionmentioning

confidence: 99%

Section: Prolonged Tcr Signaling Corresponds With Increased Expressiomentioning

confidence: 99%

TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

Das¹,

Levine

2008

The Journal of Immunology

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“…[10][11][12] In this study, we identify TSPYL2 as a component of the REST/NRSF transcriptional repressor complex and describe an important role for this complex in the regulation of the TGFβ pathway.…”

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confidence: 99%

“…10 TSPYL2 is a negative regulator of proliferation, induces p21 CDKN1A , and inhibits anchorageindependent growth; however, the mechanism through which TSPYL2 may function as a tumor suppressor is poorly understood. [10][11][12] In this study, we identify TSPYL2 as a component of the REST/NRSF transcriptional repressor complex and describe an important role for this complex in the regulation of the TGFβ pathway.…”

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confidence: 99%

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

et al. 2015

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REST/NRSF is a transcriptional repressor of neuronal genes that has been implicated in development and cancer. In epithelial tissues, REST acts as a tumor suppressor and in breast cancer, loss of REST is associated with disease recurrence and poor prognosis. Here, we identify TSPYL2 (also known as CDA1 and DENTT) as a novel component of the REST protein complex. We show that REST and TSPYL2 are regulators of TGFβ signaling and that cell-cycle arrest induced by TGFβ requires both REST and TSPYL2. Importantly, knockdown of REST or TSPYL2 resulted in transformation of human mammary epithelial cells. Mechanistically, we demonstrate that the TSPYL2/REST complex promotes TGFβ signaling by repressing the expression of genes, such as the proto-oncogene neurotrophic tyrosine kinase receptor C (TrkC). These data provide insight into the role of REST as a tumor suppressor in epithelial tissues through the regulation of the TGFβ pathway. Cell Death and Differentiation (2015) 22, 1353-1362 doi:10.1038/cdd.2014; published online 23 January 2015The transcription factor REST was originally discovered as a repressor of neuronal differentiation genes in non-neuronal lineages. Therefore, REST is considered as a master regulator of neurogenesis in development and maintenance of gene silencing. [1][2][3][4] Recently, it has been recognized that aberrant REST function also has a role in human malignancies, largely depending on the cellular context. 5 Focal genomic deletions targeting the REST locus have been found in colon adenocarcinoma and REST protein expression is often lost in small cell lung carcinoma cells. 6,7 In breast cancer, the loss of full-length (FL) REST protein is associated with disease recurrence and poor prognosis.8 However, the underlying mechanism of how REST protects against transformation in epithelial tissues has remained largely elusive.We have previously implicated the testis-specific protein, Y-encoded-like (TSPY-L) family of genes in cancer by identifying TSPYL5 expression as a prognostic marker of poor clinical outcome in breast cancer.9 TSPYL5 can interfere with p53-dependent cell-cycle arrest and oncogene-induced senescence triggering p53 ubiquitination and protein degradation.9 Besides TSPYL5, the TSPYL family of genes includes several other members (four coding genes and one pseudogene) whose functions are still unknown. All five proteins (TSPYL1, TSPYL2, TSPYL4, TSPYL5, and TSPYL6) are characterized by a predicted nucleosome assembly protein (NAP) domain, although functional evidence of NAP activity has not been reported of any of the TSPYL family members. TSPYL2, which shares only partial homology with TSPYL5, has been proposed as a candidate tumor suppressor in carcinoma cells.10 TSPYL2 is a negative regulator of proliferation, induces p21 CDKN1A , and inhibits anchorageindependent growth; however, the mechanism through which TSPYL2 may function as a tumor suppressor is poorly understood. [10][11][12] In this study, we identify TSPYL2 as a component of the REST/NRSF transcriptional repressor comple...

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“…Kindlin-2 also interacts with migfilin, a filamin and vasodilator stimulated protein (VASP)-binding protein. Kindlin-2 requires integrin-linked kinase [4] for its localization at focal adhesions [5] and in turn recruits migfilin to focal adhesion sites [6]. Due to its essential role in integrin activation, Kindlin-2 is involved in many important physiological processes, including heart development [7], cell migration [6] and cancer progression [8].…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of human Kindlin-2 core promoter identifies a key role of SP1 in Kindlin-2 transcriptional regulation

Khan

Shimokawa

Strömblad

et al. 2011

Cellular and Molecular Biology Letters

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Kindlin-2 is a recently identified FERM and PH domain containing integrin interacting protein. Kindlin-2 is ubiquitously expressed in normal tissues. So far, much effort has been spent exploring the functional aspects of Kindlin-2. However, the transcriptional regulation of Kindlin-2 has not yet been investigated. In this study we identified and functionally characterized the promoter of the human Kindlin-2 gene. We show that the core promoter of Kindlin-2 is a 39 base pair long GC rich fragment located −122/-83 upstream of the Kindlin-2 transcription start site. Functional characterization of this core promoter region by both in silico as well as in vitro/in vivo analysis shows that the transcription factor SP1 plays an important role in regulation of Kindlin-2 expression.

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Antiproliferative Autoantigen CDA1 Transcriptionally Up-regulates p21Waf1/Cip1 by Activating p53 and MEK/ERK1/2 MAPK Pathways

Cited by 60 publications

References 65 publications

TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

Functional characterization of human Kindlin-2 core promoter identifies a key role of SP1 in Kindlin-2 transcriptional regulation

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