A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways.

Horii, Yusuke; Beeler, John F.; Sakaguchi, Kazushige; Tachibana, Masayoshi; Miki, Toru

doi:10.1002/j.1460-2075.1994.tb06803.x

Cited by 194 publications

(190 citation statements)

References 39 publications

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“…Furthermore, since Lbc is reported to be an exchange factor for RhoA (Zheng et al, 1995), Brx may be expected to function as a Rho-GEF (see below). Thus, Brx represents a novel member of the Dbl family of oncoproteins (reviewed in: Cerione and Zheng, 1996) which includes: Cdc24 and Bcr (Ron et al, 1991), Vav (Adams et al, 1992;Galland et al, 1992), Ect2 (Miki et al, 1993), Ras GRF (Shou et al, 1992), Abr (Heisterkamp et al, 1993), Tim (Chan et al, 1994), FGD1 (Pasteris et al, 1994), Lbc (Toksoz and Williams, 1994), Ost (Horii et al, 1994), Tiam-1 (Habets et al, 1994), Dbs (Whitehead et al, 1995a), Lfc (Whitehead et al, 1995b) and Lsc . The Dbl oncogene was isolated using a transfection focus assay system with DNA from a patient with di use human B cell lymphoma (Eva and Aaronson, 1985), and subsequent studies have revealed the dbl oncogene and proto-dbl oncogene (Ron et al, 1988(Ron et al, , 1991 to regulate cell growth and other diverse cellular functions (Cerione and Zheng, 1996).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

et al. 1998

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Regulation of gene activation by the estrogen receptor (ER) is complex and involves co-regulatory proteins, oncoproteins (such as Fos and Jun), and phosphorylation signaling pathways. Here we report the cloning and initial characterization of a novel protein, Brx, that contains a region of identity to the oncogenic Rhoguanine nucleotide exchange (Rho-GEF) protein Lbc, and a unique region capable of binding to nuclear hormone receptors, including the ER. Western and immunohistochemistry studies showed Brx to be expressed in estrogen-responsive reproductive tissues, including breast ductal epithelium. Brx bound speci®cally to the ER via an interaction that required distinct regions of ER and Brx. Furthermore, overexpression of Brx in transfection experiments using an estrogenresponsive reporter revealed that Brx augmented gene activation by the ER in an element-speci®c and liganddependent manner. Moreover, activation of ER by Brx could be speci®cally inhibited by a dominant-negative mutant of Cdc42Hs, but not by dominant negative mutants of RhoA or Rac1. Taken together, these data suggest that Brx represents a novel modular protein that may integrate cytoplasmic signaling pathways involving Rho family GTPases and nuclear hormone receptors.

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Section: Discussionmentioning

confidence: 99%

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

et al. 1998

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“…The dbl proteins are themselves oncogenic, stimulate JNK activation and many show exchange factor activity towards the racrelated GTPases (Hart et al, 1994;Horii et al, 1994;Cerione and Zheng, 1996;Denhardt, 1996). Candidate molecules which could act upstream of these exchange factors include the src-like non-receptor tyrosine kinases, Pyk2 and the adaptor molecule shc (Dikic et al, 1996;Chen et al, 1996).…”

Section: Alpha1bmentioning

confidence: 99%

“…The ras proteins regulate a wide variety of cellular processes including growth and di erentiation, and constitutively activated ras is oncogenic. The rac proteins control cytoskeletal assembly (Tapon and Hall, 1997) and the exchange factors that activate rac are also oncogenic (Hart et al, 1994;Horii et al, 1994;Cerione and Zheng 1996) implying that like ras, rac also regulates mitogenic signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

The ras-related GTPase rac1 regulates a proliferative pathway selectively utilized by G-protein coupled receptors

et al. 1998

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Ras and rac are each members of the superfamily of monomeric GTPases and both function as molecular switches to link cell-surface signals to intracellular responses. Using a novel assay of cellular proliferation called R-SAT TM (Receptor Selection and Ampli®cation Technology), we examined the roles of ras and rac in mediating the proliferative responses to a variety of cellsurface receptors. Activated, wild-type and dominantnegative mutants of rac and ras were tested for their e ects on cellular proliferation either alone or in combination with receptors. Activated rac (rac Q61L, henceforth rac*) and ras (ras G12V, henceforth ras*) each induced strong proliferative responses. Dominantnegative rac (rac T17N, henceforth rac (7)) dramatically suppressed proliferative responses to G-protein coupled receptors (GPCR's) including the m5 muscarinic receptor and the a1B adrenergic receptor. In contrast, rac(7) had little or no e ect upon responses to the tyrosine kinase receptor TrkC, and only partially suppressed responses to the Janus kinase (JAK/STAT) linked granulocyte macrophage colony stimulating factor (GM-CSF) receptor. Dominant-negative ras (ras T17N, henceforth ras(7)) blocked the proliferative responses to all of the tested receptors. Compared to rac(7) and ras(7), wild-type rac and ras had only modest e ects on the tested receptors. Overall these results demonstrate that rac mediates the proliferative e ects of G-protein coupled receptors through a pathway that is distinct from the proliferative signaling pathway utilized by tyrosine kinase linked and JAK-linked receptors.

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“…Dbs is an exchange factor which activates RhoA and CDC42, with weaker activation of RhoG [25][26][27]. Its rat ortholog is known as Ost [28,29]. Dbs is negatively regulated by an auto-repressive N-terminal region [25,28,29] analogous to the mode of auto-regulation of the related guanine nucleotide exchange factor (GEF), Dbl [30].…”

Section: Introductionmentioning

confidence: 99%

“…Its rat ortholog is known as Ost [28,29]. Dbs is negatively regulated by an auto-repressive N-terminal region [25,28,29] analogous to the mode of auto-regulation of the related guanine nucleotide exchange factor (GEF), Dbl [30]. The natural mechanism of activation of Dbs is unknown, but apparently involves positive regulation of the catalytic GEF domain by phosphoinositide lipids binding to the adjacent PH domain [31,32].…”

Section: Introductionmentioning

confidence: 99%

The RhoA‐ and CDC42‐specific exchange factor Dbs promotes expansion of immature thymocytes and deletion of double‐positive and single‐positive thymocytes

2004

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Specific members of the Rho family of GTPases exert unique influences on thymocyte proliferation, differentiation and deletion. Dbs is a guanine nucleotide exchange factor which is expressed throughout thymocyte development and is able to activate the Rho family GTPases CDC42, RhoA and RhoG. Transgenic mice expressing an activated form of Dbs had increased numbers of double-negative thymocytes. The Dbs transgene promoted expansion of double-negative thymocytes in the absence of pre-TCR, but had no effect on pre-TCR-dependent differentiation of double-negative thymocytes into double-positive thymocytes. Transgenic double-positive thymocytes were proliferative in vivo, but were also susceptible to apoptosis in vivo and in vitro. The transgenic single-positive thymocytes had attenuated proliferative responses following TCR ligation, and were depleted rather than expanded during culture in the presence of anti-CD3. When expressing a positively selectable TCR, transgenic double-positive thymocytes were increased in number and activated, but the output of single-positive thymocytes was reduced. Transgenic double-positive thymocytes were acutely sensitive to deletion by TCR ligation in vivo. These results indicate that activation of Dbs has the potential to promote proliferation throughout thymocyte development, but also sensitizes double-positive and single-positive thymocytes to deletion.

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A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways.

Cited by 194 publications

References 39 publications

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

The ras-related GTPase rac1 regulates a proliferative pathway selectively utilized by G-protein coupled receptors

The RhoA‐ and CDC42‐specific exchange factor Dbs promotes expansion of immature thymocytes and deletion of double‐positive and single‐positive thymocytes

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