Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma

Cleverley, Steve; Costello, Patrick; Henning, Stefan; Cantrell, Doreen A.

doi:10.1038/sj.onc.1203259

Cited by 42 publications

(24 citation statements)

References 20 publications

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“…Decreased Rac1 activity is known to promote epithelial tumor cells invasion and malignant progression (Malliri et al 2002). The inactivation of RhoA potentiates the development of KRAS-induced hepatocellular carcinomas (Chew et al 2014) and favors T-cell lymphoma (Cleverley et al 2000, Yoo et al 2014. Samples from colon (n = 15), lung (n = 15), breast (n = 15), kidney (n = 15), prostate (n = 15) and bladder (n = 11) were used for quantification of FARP1, ARHGEF1 and ARHGAP36 expression variations by MRM-MS. Data are normalized to non-tumor adjacent tissue from the same patient.…”

Section: Discussionmentioning

confidence: 99%

Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

Croisé¹,

Houy²,

Gand³

et al. 2016

Endocrine-Related Cancer

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Among small GTPases from the Rho family, Cdc42, Rac, and Rho are well known to mediate a large variety of cellular processes linked with cancer biology through their ability to cycle between an inactive (GDP-bound) and an active (GTP-bound) state. Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated form, whereas the GTPase-activating proteins (GAPs) catalyze GTP hydrolysis, leading to the inactivated form. Modulation of Rho GTPase activity following altered expression of Rho-GEFs and/or Rho-GAPs has already been reported in various human tumors. However, nothing is known about the Rho GTPase activity or the expression of their regulators in human pheochromocytomas, a neuroendocrine tumor (NET) arising from chromaffin cells of the adrenal medulla. In this study, we demonstrate, through an ELISA-based activity assay, that Rac1 and Cdc42 activities decrease in human pheochromocytomas (PCCs) compared with the matched adjacent non-tumor tissue. Furthermore, through quantitative mass spectrometry (MS) approaches, we show that the expression of two Rho-GEF proteins, namely ARHGEF1 and FARP1, is significantly reduced in tumors compared with matched non-tumor tissue, whereas ARHGAP36 expression is increased. Moreover, siRNA-based knockdown of ARHGEF1 and FARP1 in PC12 cells leads to a significant inhibition of Rac1 and Cdc42 activities, respectively. Finally, a principal component analysis (PCA) of our dataset was able to discriminate PCC from non-tumor tissue and indicates a close correlation between Cdc42/Rac1 activity and FARP1/ARHGEF1 expression. Altogether, our findings reveal for the first time the importance of modulation of Rho GTPase activities and expression of their regulators in human PCCs. 23:4Research 281-293 P Croisé et al.Rho-GTPase activity in human pheochromocytoma

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Section: Discussionmentioning

confidence: 99%

Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

Croisé¹,

Houy²,

Gand³

et al. 2016

Endocrine-Related Cancer

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“…12,13 Although their exact role in human T-cell transformation remains uncertain, RHOA mutations tend to co-occur with TET2 mutations, suggesting that they represent a second event in multistep AITL lymphomagenesis. 15 Finally, AITL also bears a variety of other less recurrent genetic alterations. 12,13,16 In B-cell lymphomas, constitutive B-cell receptor (BCR) signaling via somatic mutation-induced or antigen-mediated activation of key BCR components leads to neoplastic B-cell survival and expansion.…”

Section: Introductionmentioning

confidence: 99%

Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell–derived lymphomas

Vallois

Dobay

Morin

et al. 2016

Blood

270

292

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“…Recent studies have suggested that Rho proteins also have regulatory functions in immune cell populations. For example, Rho-GTPases have been implicated in the regulation of cell shape in a T cell line (11,12) and in thymocyte homeostasis in transgenic mice (13,14). In addition, experiments in Jurkat cells have suggested a contribution of Rho in promoting IL-2 production and calcium influx (15).…”

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confidence: 99%

Rho Kinase Promotes Alloimmune Responses by Regulating the Proliferation and Structure of T Cells

Tharaux

Bukoski

Rocha

et al. 2003

The Journal of Immunology

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Coordinated rearrangements of the actin-myosin cytoskeleton facilitate early and late events in T cell activation and signal transduction. As many important features of cell shape rearrangement involve small GTP-binding proteins, we examined the contribution of Rho kinase to the functions of mature T cells. Inhibitors of the Rho kinase pathway all had similar actions to inhibit the proliferation of primary lymphocyte cultures. Likewise, transfection of the human Jurkat T cell line with a dominant negative, kinase-defective mutant of Rho kinase diminished Jurkat cell proliferation. Furthermore, inhibition of Rho kinase substantially attenuated the program of cytokine gene expression that characterizes T cell activation, blocked actomyosin polymerization, and prevented aggregation of the TCR/CD3 complex colocalized with lipid rafts. These actions are relevant to immune responses in vivo, as treatment with a Rho kinase inhibitor considerably prolonged the survival of fully allogeneic heart transplants in mice and diminished intragraft expression of cytokine mRNAs. Thus, Rho GTPases acting through Rho kinase play a unique role in T cell activation during cellular immune responses by promoting structural rearrangements that are critical for T cell signaling.

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Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma

Cited by 42 publications

References 20 publications

Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell–derived lymphomas

Rho Kinase Promotes Alloimmune Responses by Regulating the Proliferation and Structure of T Cells

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