Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway

Freed-Pastor, William A.; Mizuno, Hideaki; Zhao, Xi; Langerød, Anita; Moon, Sung; Rodríguez-Barrueco, Ruth; Barsotti, Anthony M.; Chicas, Agustin; Li, Wencheng; Polotskaia, Alla; Bissell, Mina J.; Osborne, Timothy F.; Tian, Bin; Lowe, Scott W.; Silva, José M.; Børresen-Dale, Anne Lise; Levine, Arnold J.; Bargonetti, Jill; Prives, Carol

doi:10.1016/j.cell.2011.12.017

Cited by 731 publications

(829 citation statements)

References 80 publications

(72 reference statements)

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“…In pure cultures of gd T cells, zoledronate was extremely toxic. Addition of GGPP, which can restore protein prenylation despite inhibition of mevalonate metabolism (1,29,30), eliminated zoledronate toxicity. Further supplementation with IL-18 was sufficient to enable a vigorous proliferative response of gd T cells in the absence of any other accessory cells.…”

Section: Discussionmentioning

confidence: 99%

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Nussbaumer

Gruenbacher

Gander

et al. 2013

The Journal of Immunology

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The potent nitrogen-containing bisphosphonate zoledronate inhibits farnesyl pyrophosphate synthase, a key enzyme of the mevalonate pathway that is often hyperactive in malignant cells. Zoledronate activates human Vγ9Vδ2 T cells, which are immune sentinels of cell stress and tumors, through upstream accumulation of the cognate Ag isopentenyl pyrophosphate. IL-18 was shown to enhance zoledronate-induced γδ T cell activation. Although monocytes have been considered important accessory cells that provide the Ag isopentenyl pyrophosphate, CD56brightCD11c+ NK cells were postulated to mediate the costimulatory effects of IL-18. We report in this article that downstream depletion of geranylgeranyl pyrophosphate (GGPP), which is required for protein prenylation, caused cell stress in monocytes, followed by caspase-1–mediated maturation and release of IL-18, which, in turn, induced γδ T cell CCL2. Likewise, zoledronate caused a substantial delay in γδ T cell expansion, which could be skipped by GGPP supplementation. Moreover, repletion of GGPP, which prevented acute zoledronate toxicity, and supplementation with IL-18, which strongly upregulated IL-2Rα (CD25) and favored the central memory phenotype, were sufficient to enable zoledronate-induced expansion of highly purified γδ T cells, even when starting cell numbers were as low as 104 γδ T cells. Our study reveals essential components of γδ T cell activation and indicates that exogenous IL-18, which can directly costimulate γδ T cells, eliminates the need for any accessory cells. Our findings will facilitate the generation of robust γδ T cells from small blood or tissue samples for cancer immunotherapy and immune-monitoring purposes.

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Section: Discussionmentioning

confidence: 99%

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Nussbaumer

Gruenbacher

Gander

et al. 2013

The Journal of Immunology

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“…Les mutations de p53 aggravent cette situation : elles entraînent souvent la souris p53 -/-, la régression des lymphomes T consécutive à l'activation de p63 ou p73 et l'expression de iapp, ne soit pas directement provoquée par la reprogrammation métabolique des cellules tumorales, mais par l'apoptose qui l'accompagne [10]. Une conséquence importante de la dualité fonctionnelle de p53 est que si la cellule ne « voit » pas sa transformation oncogénique, soit La régulation négative par p53 normal de la voie du mévalonate est probable mais pas établie [7,50]. L'effet sur la voie des pentoses phosphates est ambivalent puisque p53 la stimule via l'activation du gène tigar, et la réprime via l'inhibition de la glucose 6 phosphate déshydrogénase (G6PD).…”

Section: Conclusion Perspectivesunclassified

“…D'autres mutants peuvent agir comme co-activateurs des facteurs de transcription SREBP (sterol-regulatory element-binding protein), alors que p53 normale réprime l'expression du gène codant SREBP-1. Cette activité confère aux mutants la capacité de stimuler la voie du mévalonate et la synthèse des acides gras [7,50]. L'effet des mutants oncogéniques de p53 sur la phosphorylation oxydative et la voie des pentoses phosphates reste à préciser (flèches noires).…”

Section: Conclusion Perspectivesunclassified

“…Notons que le p53 mutant de la figure est une synthèse cumulant les fonctions métaboliques de plusieurs mutants oncogéniques différents. L'un d'eux cependant, p53 R273H , stimule l'effet Warburg, la voie du mévalonate et n'inhibe pas la G6PD [21,49,50] Quelle est l'importance relative des différents aspects du contrôle du métabolisme par p53 pour la suppression tumorale ?…”

Section: Conclusion Perspectivesunclassified

“…De plus, des allèles de p53 fréquemment associés aux cancers humains présentent de nouvelles propriétés (mutants néomorphes) participant activement à la transformation (Figure 4) [1,4,5]. Ainsi, plusieurs mutations ponctuelles altèrent ou inversent les fonctions métaboliques de p53 : les mutants correspondants promeuvent l'effet Warburg et/ou la voie du méva-lonate et la synthèse des acides gras, ce qui contribue à leur effet tumorigène [48][49][50] (Tableau II) (Figure 5). Il apparaît donc que les multiples influences de p53 sur le métabolisme et la survie cellulaire, sa capacité à moduler la stabilité génétique, et sa propension à acquérir une nouvelle fonction par un seul changement d'acide aminé, en font aussi un outil de choix pour la « gymnastique oncogénétique » [15] permettant aux cellules tumorales de s'adapter et croître dans des environnements variables et souvent défavorables.…”

Section: Conclusion Perspectivesunclassified

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Protéger et sévir : p53, métabolisme et suppression tumorale

Albagli

2015

Med Sci (Paris)

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Biochemical pathways mediated by KLK6 protease in breast cancer

et al. 2019

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Kallikrein‐related peptidase 6 (KLK6) is a serine protease normally expressed in mammary tissue and aberrantly regulated in breast cancer. At physiological levels, KLK6 functions as a suppressor of breast cancer, while its aberrant overexpression (> 50‐fold higher than normal) is characteristic of a subset of breast cancers and has been linked to accelerated growth of primary breast tumors in severe combined immunodeficiency mice (Pampalakis et al. Cancer Res 2009, 69, 3779). Here, we investigated the molecular mechanisms underlying the concentration‐dependent functions of KLK6 by comparing MDA‐MB‐231 stable transfectants expressing increasing levels of KLK6 in in vitro and in vivo tumorigenicity assays (soft agar, xenograft growth, tail vein metastasis). Quantitative proteomics was applied to identify proteins that are altered upon re‐expression of KLK6 in MDA‐MB‐231 at normal or constitutive levels. Overexpression of KLK6 is associated with increased metastatic ability of breast cancer cells into lungs, increased expression of certain S100 proteins (S100A4, S100A11) and keratins (KRT), and downregulation of the apoptosis‐related proteases CASP7 and CASP8, and RABs. On the other hand, KLK6 re‐expression at physiological levels leads to inhibition of lung metastases associated with suppression of S100 proteins (S100A4, S100A10, S100A13, S100A16) and induced CASP7 and CASP8 expression. As this is the first report that KLK6 expression is associated with S100 proteins, caspases, RABs, and KRTs, we validated this finding in clinical datasets. By integrating proteomics and microarray data from breast cancer patients, we generated two composite scores, KLK6 + S100B‐S100A7 and KLK6 + S100B‐S100A14‐S100A16, to predict long‐term survival of breast cancer patients. We present previously unknown pathways implicating KLK6 in breast cancer. The findings promise to aid our understanding of the functional roles of KLK6 in breast cancer and may yield new biomarkers for the cancer types in which KLK6 is known to be aberrantly upregulated.

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Mutant p53 Disrupts Mammary Tissue Architecture via the Mevalonate Pathway

Cited by 731 publications

References 80 publications

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

Protéger et sévir : p53, métabolisme et suppression tumorale

Biochemical pathways mediated by KLK6 protease in breast cancer

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