Cyclin-dependent kinase inhibitor p21Waf1: Contemporary view on its role in senescence and oncogenesis

Romanov, Victor; Поспелов, В. А.; Поспелова, Т. В.

doi:10.1134/s000629791206003x

Cited by 108 publications

(97 citation statements)

References 114 publications

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“…GADD45A and CDKN1A (p21), both of which regulate cell cycle arrest 28,29 and are induced by p53, were significantly upregulated in v2-depleted cells compared with controls in a p53+, but not p53i, background (Figure 4d and Supplementary Figure S3B), suggesting they may contribute to the p53-dependent S-phase arrest in v2-depleted cells. On the other hand, proliferating cell nuclear antigen (PCNA), which is required for progression of DNA replication, 30 was significantly reduced in TP8i cells in both the p53+ and p53i settings ( Figure 5e).…”

Section: Resultsmentioning

confidence: 90%

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

et al. 2016

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Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a stress-response gene that has been associated with cancer, but no studies have differentiated among or defined the regulation or function of any of its several recently described expression variants. We found that TNFAIP8 variant 2 (v2) is overexpressed in multiple human cancers, whereas other variants are commonly downregulated in cancer (v1) or minimally expressed in cancer or normal tissue (v3-v6). Silencing v2 in cancer cells induces p53-independent inhibition of DNA synthesis, widespread binding of p53, and induction of target genes and p53-dependent cell cycle arrest and DNA damage sensitization. Cell cycle arrest induced by v2 silencing requires p53-dependent induction of p21. In response to the chemotherapeutic agent doxorubicin, p53 regulates v2 through binding to an intragenic enhancer, together indicating that p53 and v2 engage in complex reciprocal regulation. We propose that TNFAIP8 v2 promotes human cancer by broadly repressing p53 function, in essence offsetting p53-dependent tumor suppression. Cell Death and Differentiation (2017) 24, 181-191; doi:10.1038/cdd.2016 published online 11 November 2016 Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is the founding member of a recently described family of environmental stress response genes that are induced by TNFα. TNFAIP8 has been shown to promote or inhibit apoptosis, depending on cell type and context. 1,2 Although little is known about TNFAIP8, it has recently been found to be overexpressed in a wide range of human cancers. Some studies have suggested protumor functions for TNFAIP8, including enhancement of cell survival, proliferation, and metastasis [3][4][5][6][7][8][9] and resistance to cancer chemotherapeutics in mice. 4,10Nonetheless, nothing is known about how TNFAIP8 influences responses to DNA damage in cancer cells. Moreover, several transcript variants from the TNFAIP8 gene were recently registered in the NCBI reference sequence database, but no study to date has differentiated among them or defined the factors that govern their expression.The tumor suppressor p53 is a transcription factor that regulates many biological processes through its target gene network. Some of the well-characterized p53 target genes including p21/CDKN1A, growth arrest and DNA damageinducible 45a (GADD45A) and Bcl-2-like protein 4 (BAX) together promote senescence, cell cycle arrest, and apoptosis, all of which may contribute to the tumor suppressing functions of p53. 11,12Additional noncanonical tumorsuppressive pathways from p53 have recently been identified. [13][14][15] Improved characterization of the p53 DNAbinding sequence with modern sequencing techniques has led to the identification of a rapidly expanding list of p53 target genes. [16][17][18] Continued identification of these genes and characterization of their mechanisms of regulation and function will be critical to a full understanding of p53 and for full realization of opportunities to intervene upon p53 in cancer.Here, we identify ...

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Section: Resultsmentioning

confidence: 90%

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

et al. 2016

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“…p21/WAF1 is also known as cyclindependent kinase (CDK) inhibitor 1 or CDK-interacting protein 1. p21/WAF1 is a cell cycle checkpoint, where cells either set about repairing themselves or commit suicide through apoptosis (52,53). The p21/WAF1 protein functions as a regulator of cell cycle progression at the G1 phase by inhibiting cyclin-CDK2 or -CDK1 activity (52,54,55).…”

Section: +mentioning

confidence: 99%

S100 family signaling network and related proteins in pancreatic cancer (Review)

Huang

Jiang

et al. 2014

International Journal of Molecular Medicine

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Abstract. The occurrence and development of pancreatic cancer is a complex process convoluted by multi-pathogenies, multi-stages and multi-factors. S100 proteins are members of the S100 family that regulate multiple cellular pathways related to pancreatic cancer progression and metastasis. S100 proteins have a broad range of intracellular and extracellular functions, including the regulation of protein phosphorylation and enzyme activity, calcium homeostasis and the regulation of cytoskeletal components and transcriptional factors. S100 proteins interact with receptor for advanced glycation end-products (RAGE), p53 and p21, which play a role in the degradation of the extracellular matrix (ECM) and metastasis, and also interact with cytoskeletal proteins and the plasma membrane in pancreatic cancer progression and metastasis. S100A11 and S100P are significant tumor markers for pancreatic cancer and unfavorable predictors for the prognosis of patients who have undergone surgical resection. Recently, S100A2 has been suggested to be a negative prognostic biomarker in pancreatic cancer, and the expression of S100A6 may be an independent prognostic impact factor. The expression of S100A4 and S100P is associated with drug resistance, differentiation, metastasis and clinical outcome. This review summarizes the role and significance of the S100 family signaling network and related proteins in pancreatic cancer.

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“…Depending on its subcellular localization, p21 Cip1 displays diverse activities with respect to proliferation (Romanov et al, 2012). Using co-immunofluorescence with the germ cell marker Tra98, we found that p21…”

Section: Cip1mentioning

confidence: 99%

Prostaglandin D2 acts through the Dp2 receptor to influence male germ cell differentiation in the foetal mouse testis

et al. 2014

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Through intercellular signalling, the somatic compartment of the foetal testis is able to program primordial germ cells to undergo spermatogenesis. Fibroblast growth factor 9 and several members of the transforming growth factor β superfamily are involved in this process in the foetal testis, counteracting the induction of meiosis by retinoic acid and activating germinal mitotic arrest. Here, using in vitro and in vivo approaches, we show that prostaglandin D 2 (PGD 2 ), which is produced through both L-Pgds and H-Pgds enzymatic activities in the somatic and germ cell compartments of the foetal testis, plays a role in mitotic arrest in male germ cells by activating the expression and nuclear localization of the CDK inhibitor p21Cip1 and by repressing pluripotency markers. We show that PGD 2 acts through its Dp2 receptor, at least in part through direct effects in germ cells, and contributes to the proper differentiation of male germ cells through the upregulation of the master gene Nanos2. Our data identify PGD 2 signalling as an early pathway that acts in both paracrine and autocrine manners, and contributes to the differentiation of germ cells in the foetal testis.

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Cyclin-dependent kinase inhibitor p21Waf1: Contemporary view on its role in senescence and oncogenesis

Cited by 108 publications

References 114 publications

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

S100 family signaling network and related proteins in pancreatic cancer (Review)

Prostaglandin D2 acts through the Dp2 receptor to influence male germ cell differentiation in the foetal mouse testis

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