The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase

Passer, Brent J.; Nancy-Portebois, Vanessa; Amzallag, Nathalie; Prieur, Sylvie; Cans, Christophe; Climens, Aude Roborel de; Fiucci, Giusy; Bouvard, Véronique; Tuynder, Marcel; Susini, Laurent; Morchoisne, Stephanie; Crible, Virginie; Lespagnol, Alexandra; Dausset, J; Oren, Moshe; Amson, Robert; Telerman, Adam

doi:10.1073/pnas.0530298100

Cited by 111 publications

(126 citation statements)

References 35 publications

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“…In addition p53 activation can enhance the rate of exosome production by the damaged cell by inducing the p53-regulated TSAP-6 gene. 56,61 Exosomes can communicate with adjacent cells by cell fusion and with T cells by presenting antigens to the immune system. Could p53-mediated apoptosis enhance immunization of the host in this fashion?…”

Section: The Cellular Outputs Of the Downstream Eventsmentioning

confidence: 99%

The P53 pathway: what questions remain to be explored?

2006

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The p53 pathway is composed of hundreds of genes and their products that respond to a wide variety of stress signals. These responses to stress include apoptosis, cellular senescence or cell cycle arrest. In addition the p53-regulated genes produce proteins that communicate these stress signals to adjacent cells, prevent and repair damaged DNA and create feedback loops that enhance or attenuate p53 activity and communicate with other signal transduction pathways. Many questions remain to be explored in our understanding of how this network of genes plays a role in protection from cancers, therapy and integrating the homeostatic mechanisms of stress management and fidelity in a cell and organism. The goal of this chapter is to elucidate some of those questions and suggest new directions for this area of research.

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Section: The Cellular Outputs Of the Downstream Eventsmentioning

confidence: 99%

The P53 pathway: what questions remain to be explored?

2006

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“…Whereas STEAP, STAMP1 and STAMP2 genes are located as a gene cluster on Chr7q in humans, (25) STAMP3 is located on chromosome 2 and was initially cloned as a p53-inducible gene. (26) STEAP lacks the N-terminal half present in the STAMPs and is therefore likely to have a different function compared with other members of the family. (27) STAMP1 is highly restricted to prostate for expression and is overexpressed in prostate cancer compared with benign prostate tissue.…”

Section: Stamp Familymentioning

confidence: 99%

“…(31) Consistent with this, TSAP6 knockdown in cell lines inhibited p53-induced apoptosis and this appears to be due to TSAP6 association with Nix, a proapoptotic Bcl-2-related protein and the Myt1 kinase, a negative regulator of the G 2 /M transition. (26) In addition to their six transmembrane domains in the C terminus, STAMPs have a putative oxidoreductase domain in their N terminus, which may function as iron and/or copper reductases, at least in some cell types. (32) The exact function of STAMPs and their mechanism of action in prostate cancer cells and whether they can be utilized as markers or therapeutic targets remain to be explored.…”

Section: Stamp Familymentioning

confidence: 99%

Androgen signaling and its interactions with other signaling pathways in prostate cancer

2007

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SummaryProstate cancer is the most frequently diagnosed nonskin cancer and the third leading cause of cancer mortality in men. In the initial stages, prostate cancer is dependent on androgens for growth, which is the basis for androgen ablation therapy. However, in most cases, prostate cancer progresses to a hormone refractory phenotype for which there is no effective therapy available at present. The androgen receptor (AR) is required for prostate cancer growth in all stages, including the relapsed, ''androgen-independent'' tumors in the presence of very low levels of androgens. This review focuses on AR function and AR-target genes and summarizes the major signaling pathways implicated in prostate cancer progression, their crosstalk with each other and with AR signaling. This complex network of interactions is providing a deeper insight into prostate carcinogenesis and may form the basis for novel diagnostic and therapeutic strategies. IntroductionProstate adenocarcinoma is the most frequently diagnosed non-cutaneous male malignancy and the third leading cause of cancer-related death in men in most western industrialized countries. (1) It is estimated that around 660,000 men worldwide will be diagnosed with prostate cancer and 250,000 men will die from it in 2010; thus, it will remain a major health problem in the future. (1) It was more than 60 years ago that the important role of male sex hormones (androgens) for the development and growth of prostate cancer was demonstrated. (2) Accordingly, androgen ablation therapy has been the main line of therapy for prostate cancer. Therefore, much of the focus in prostate cancer research to date has naturally been on androgens, how to decrease the androgens in the circulation and how to inhibit the androgen receptor (AR).In addition to AR signaling, it has now become evident that other signaling pathways, as well as non-genomic and genomic alterations, are involved in prostate cancer development and progression. Furthermore, recent studies indicated that signaling through AR has a critical role even after androgen ablation and disease progression (for review see Ref.3). In the following sections, we give an overview of androgen signaling in prostate cancer, with a special focus on recent findings about AR function and AR target genes. We then review the involvement of other central signaling pathways in prostate cancer, with a special focus on their cross-talk with the AR signaling pathway. Clinical implications of these findings and potential directions for future research are also outlined.

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“…1,2 Its promoter contains a functional p53-responsive element. 3 TSAP6 is part of a family of oxydoreductases with six transmembrane domains 4 and was recently identified as a ferrireductase (Steap3). 5 TSAP6 knockdown results in inhibition of apoptosis.…”

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confidence: 99%

“…5 TSAP6 knockdown results in inhibition of apoptosis. 3 It binds to 3 and cooperates with Nix, a proapoptotic, BH3-only, Bcl2 familymember and Myt1 kinase, a negative regulator of the G 2 M transition.…”

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Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice

et al. 2008

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TSAP6 (tumor suppressor-activated pathway 6), also known as Steap3, is a direct p53 transcriptional target gene. It regulates protein secretion, for example translationally controlled tumor protein (TCTP), which is implicated in tumor reversion. In keeping with the latter, we show herein that TSAP6 is a glycosylated protein present in the trans-Golgi network, endosomal-vesicular compartment and cytoplasmic membrane. To further investigate the physiological function of TSAP6, we have generated TSAP6-deficient mice. These mice exhibit microcytic anemia with abnormal reticulocyte maturation and deficient transferrin receptor downregulation, a process known to be dependent on exosomal secretion. Moreover, we provide direct evidence that exosome production is severely compromised in TSAP6-null cells. Finally, we show that the DNA damage-induced p53-dependent nonclassical exosomal secretory pathway is abrogated in TSAP6-null cells. Given the fact that exosomes are used as cell-free vaccines against cancer and that they could be involved in the biogenesis and spread of human immunodeficiency virus, it is important to understand their regulation. The results presented here provide the first genetic demonstration that exosome formation is a tightly controlled biological process dependent of TSAP6.

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The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase

Cited by 111 publications

References 35 publications

The P53 pathway: what questions remain to be explored?

The P53 pathway: what questions remain to be explored?

Androgen signaling and its interactions with other signaling pathways in prostate cancer

Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice

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