Signal Transducer and Activator of Transcription-5 Mediates Neuronal Apoptosis Induced by Inhibition of Rac GTPase Activity

Stankiewicz, Trisha R.; Loucks, F. Alexandra; Schroeder, Emily K.; Nevalainen, Marja T.; Tyler, Kenneth L.; Aktories, Klaus; Bouchard, Ron J.; Linseman, Daniel A.

doi:10.1074/jbc.m111.302166

Cited by 25 publications

(23 citation statements)

References 64 publications

(39 reference statements)

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“…ToxB monoglucosylates a key threonine residue in the switch 1 region of Rho GTPases, preventing Rho, Rac, and Cdc42 from interacting with their downstream effectors (7). Global inhibition of Rho GTPases with ToxB induces CGN apoptosis through dysregulation of critical prosurvival and proapoptotic signaling cascades (8,9). Specifically, ToxB induces down-regulation of Rac1 GTPase as well as elements of a Racdependent mitogen-activated protein (MAP) kinase pathway, including the p21-activated kinase (PAK), MEK1/2, and ERK1/2 signaling cascade.…”

Section: Rho Family Gtpases Play Integral Roles In Neuronal Differentmentioning

confidence: 99%

Neuronal Apoptosis Induced by Selective Inhibition of Rac GTPase versus Global Suppression of Rho Family GTPases Is Mediated by Alterations in Distinct Mitogen-activated Protein Kinase Signaling Cascades

Stankiewicz

Ramaswami

Bouchard

et al. 2015

Journal of Biological Chemistry

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Background: Rac GTPase is essential for the survival of primary cerebellar granule neurons (CGNs). Results: NSC23766-mediated Rac inhibition induces CGN apoptosis through deactivation of prosurvival MEK5/ERK5 signaling. Conclusion: Targeted inhibition of Rac versus global inhibition of Rho GTPases induces apoptosis via disruption of unique MAP kinase signaling pathways. Significance: Elucidating the pathways that mediate neuronal apoptosis is critical for understanding the pathology of neurodegenerative diseases.

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Section: Rho Family Gtpases Play Integral Roles In Neuronal Differentmentioning

confidence: 99%

Neuronal Apoptosis Induced by Selective Inhibition of Rac GTPase versus Global Suppression of Rho Family GTPases Is Mediated by Alterations in Distinct Mitogen-activated Protein Kinase Signaling Cascades

Stankiewicz

Ramaswami

Bouchard

et al. 2015

Journal of Biological Chemistry

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“…Although the JAK2/STAT5 pathway has been classically associated with antiapoptotic and proliferative effects in other tissues [26, 34-38], it has been shown that this pathway may also mediate proapoptotic effects, probably due to the regulation of Bcl-2 protein family expression [22, 23]. We evaluated whether PRL-induced apoptosis involved the control of Bcl-2 and Bax protein levels and whether this control is mediated by STAT5 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, the JAK2/STAT5 pathway has been shown to transduce apoptotic signals when activated by other receptors or cascades. For example, in cerebellar neurons, STAT5 activation following Rac inhibition induces apoptosis [23]. One member of the IL-6 cytokine family, oncostatin M, induces apoptosis of osteosarcoma and adrenocortical cell lines via STAT5 activation [48].…”

Section: Discussionmentioning

confidence: 99%

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JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

et al. 2018

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Prolactinomas are increasingly viewed as a “problem of signal transduction.” Consequently, the identification of factors and signaling pathways that control lactotrope cell turnover is needed in order to encourage new therapeutic developments. We have previously shown that prolactin (PRL) acts as a proapoptotic and antiproliferative factor on lactotropes, maintaining anterior pituitary cell homeostasis, which contrasts with the classical antiapoptotic and/or proliferative actions exerted by PRL in most other target tissues. We aimed to investigate the PRLR-triggered signaling pathways mediating these nonclassical effects of PRL in the pituitary. Our results suggest that (i) the PRLR/Jak2/STAT5 pathway is constitutively active in GH3 cells and contributes to PRL-induced apoptosis by increasing the Bax/Bcl-2 ratio, (ii) PRL inhibits ERK1/2 and Akt phosphorylation, thereby contributing to its proapoptotic effect, and (iii) the PI3K/Akt pathway participates in the PRL-mediated control of lactotrope proliferation. We hypothesize that the alteration of PRL actions in lactotrope homeostasis due to the dysregulation of any of the mechanisms of actions described above may contribute to the pathogenesis of prolactinomas.

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“…For example, the induction of apoptosis by oncostatin M (another hematopoietic cytokine structurally close to PRL) in osteosarcoma cells requires functional STAT5 to regulate Bax/Bcl-2 ratio [58]. Similarly, activation of Jak2/STAT5 pathway in rat cerebella granule neurons induces apoptosis, also by regulating the expression of Bcl-2 family proteins [59]. In fact, the ultimate effects of PRL in a given tissue depend on many parameters including the PRLR isoform(s) that is(are) expressed and the particular physiological context.…”

Section: Prolactin Actions In the Pituitarymentioning

confidence: 99%

Use of Prolactin Receptor Antagonist to Better Understand Prolactin Regulation of Pituitary Homeostasis

Ferraris

Bernichtein²,

Pisera

et al. 2013

Neuroendocrinology

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The anterior pituitary is permanently regulated by processes of apoptosis and proliferation in order to maintain tissue homeostasis. Several factors have been implicated in this regulation and lately, prolactin (PRL) has been included into that list. However, since PRL is secreted by anterior pituitary lactotropes, the actual outcome of its autocrine/paracrine actions on pituitary cells has remained difficult to assess. The availability of the pure PRL receptor antagonist Del1-9-G129R-hPRL has been helpful to circumvent this problem. While PRL has been traditionally associated with increased cell proliferation, recent studies revealed that this hormone actually induces apoptosis and decreases proliferation of anterior pituitary cells, by mechanisms involving the PRL receptor. The aim of this short review is to overview our current understanding of the regulation of pituitary homeostasis by PRL. Moreover, studies involving Del1-9-G129R-hPRL have helped anticipate to what extent future treatments involving PRL receptor inhibitors may interfere with processes regulated by PRL at the central level.

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Signal Transducer and Activator of Transcription-5 Mediates Neuronal Apoptosis Induced by Inhibition of Rac GTPase Activity

Cited by 25 publications

References 64 publications

Neuronal Apoptosis Induced by Selective Inhibition of Rac GTPase versus Global Suppression of Rho Family GTPases Is Mediated by Alterations in Distinct Mitogen-activated Protein Kinase Signaling Cascades

Neuronal Apoptosis Induced by Selective Inhibition of Rac GTPase versus Global Suppression of Rho Family GTPases Is Mediated by Alterations in Distinct Mitogen-activated Protein Kinase Signaling Cascades

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

Use of Prolactin Receptor Antagonist to Better Understand Prolactin Regulation of Pituitary Homeostasis

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