Rac and Cdc42 Are Potent Stimulators of E2F-dependent Transcription Capable of Promoting Retinoblastoma Susceptibility Gene Product Hyperphosphorylation

Gjoerup, Ole; Lukáš, Jiří; Bártek, Jiří; Willumsen, Berthe M.

doi:10.1074/jbc.273.30.18812

Cited by 71 publications

(66 citation statements)

References 52 publications

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“…Second, Rac prolongs proliferation of cardioblasts, as shown by both Ki67 and BrdU staining (Figure 9). This result is in line with the cardiac phenotype of RhoGDI-overexpressing mice (Wei et al, 2002) and with the expected effect of Rac on cyclin D1 (Coleman and Marshall, 2001), E2F stimulation and pRb hyperphosphorylation (Gjoerup et al, 1998).…”

Section: Discussionsupporting

confidence: 72%

A Dual Role of the GTPase Rac in Cardiac Differentiation of Stem Cells

Pucéat¹,

Travo²,

Quinn³

et al. 2003

MBoC

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The function of the GTPase Rac1, a molecular switch transducing intracellular signals from growth factors, in differentiation of a specific cell type during early embryogenesis has not been investigated. To address the question, we used embryonic stem (ES) cells differentiated into cardiomyocytes, a model that faithfully recapitulates early stages of cardiogenesis. Overexpression in ES cells of a constitutively active Rac (RacV12) but not of an active mutant (RacL61D38), which does not activate the NADPH oxydase generating ROS, prevented MEF2C expression and severely compromised cardiac cell differentiation. This resulted in poor expression of ventricular myosin light chain 2 (MLC2v) and its lack of insertion into sarcomeres. Thus ES-derived cardiomyocytes featured impaired myofibrillogenesis and contractility. Overexpression of MEF2C or addition of catalase in the culture medium rescued the phenotype of racV12 cells. In contrast, RacV12 specifically expressed in ES-derived ventricular cells improved the propensity of cardioblasts to differentiate into beating cardiomyocytes. This was attributed to both a facilitation of myofibrillogenesis and a prolongation in their proliferation. The dominant negative mutant RacN17 early or lately expressed in ES-derived cells prevented myofibrillogenesis and in turn beating of cardiomyocytes. We thus suggest a stage-dependent function of the GTPase during early embryogenesis.

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Section: Discussionsupporting

confidence: 72%

A Dual Role of the GTPase Rac in Cardiac Differentiation of Stem Cells

Pucéat¹,

Travo²,

Quinn³

et al. 2003

MBoC

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“…Introduction of constitutively active Rac1 or Cdc42 mutants into NIH-3T3 fibroblasts results in increased pRb phosphorylation, E2F transcriptional activity, and cyclin D1 expression (Gjoerup et al, 1998). In addition, Rat1 fibroblasts expressing a constitutively active Rac1 mutant display significantly increased proliferation as well as a partial loss of contact inhibition (Qiu et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21CIP1 levels in androgen-independent human prostate cancer cells

et al. 2004

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Abnormally suppressed levels of cyclin-dependent kinase inhibitors (CKIs) are associated with aggressive androgenindependent prostate cancer and contribute to uncontrolled proliferation. The androgen-independent human prostate cancer cell lines, LNCaP-104R1, ALVA31 and PC-3, express low levels of the CKI, p21 CIP1 , compared to the less-malignant, androgen-dependent LNCaP cells. We investigated the mechanism underlying this suppression by examining the role of Rho GTPases, signaling proteins that play important roles in cell cycle progression, at least in part through regulation of CKIs. Inhibition of Rac1 induced p21 expression in androgen-independent lines but had no effect on the higher p21 levels characteristic of LNCaP cells. This induction of p21 was functionally significant as evidenced by inhibition of cyclin-dependent kinase 2 activity and decreased cell proliferation. Conversely, overexpression of constitutively active Rac1 suppressed the higher p21 levels seen in LNCaP cells. Thus, Rac1 activity is both necessary and sufficient for suppression of p21 in prostate cancer cells. Furthermore, Rac1 activity was significantly higher in all three androgen-independent cell lines compared to LNCaP cells. Thus in three models of aggressive human prostate cancer, hyperactivity of Rac1 corresponds to suppressed levels of p21. These results are unique in describing a role for Rac1 in p21 regulation and may implicate the Rac1 signaling pathway as a potential therapeutic target for controlling prostate cancer cell growth following progression to androgen independence.

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“…ErbB-dependent upregulation of the SP1 transcription factor has been independently reported . Cyclin D1 can be upregulated by activated Ras, Raf, MEK and Rac, all downstream targets of ErbBsignaling cascades (Albanese et al, 1995;Aziz et al, 1999;Cheng et al, 1998;Gartel et al, 2000;Gjoerup et al, 1998).…”

Section: The Cyclin D Connectionmentioning

confidence: 99%

Molecular mechanisms underlying ErbB2/HER2 action in breast cancer

2000

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Overexpression of ErbB2, a receptor-like tyrosine kinase, is shared by several types of human carcinomas. In breast tumors the extent of overexpression has a prognostic value, thus identifying the oncoprotein as a target for therapeutic strategies. Already, antibodies to ErbB2 are used in combination with chemotherapy in the treatment of metastasizing breast cancer. The mechanisms underlying the oncogenic action of ErbB2 involve a complex network in which ErbB2 acts as a ligand-less signaling subunit of three other receptors that directly bind a large repertoire of stroma-derived growth factors. The major partners of ErbB2 in carcinomas are ErbB1 (also called EGFR) and ErbB3, a kinase-defective receptor whose potent mitogenic action is activated in the context of heterodimeric complexes. Why ErbB2-containing heterodimers are relatively oncopotent is a function of a number of processes. Apparently, these heterodimers evade normal inactivation processes, by decreasing the rate of ligand dissociation, internalizing relatively slowly and avoiding the degradative pathway by returning to the cell surface. On the other hand, the heterodimers strongly recruit survival and mitogenic pathways such as the mitogen-activated protein kinases and the phosphatidylinositol 3-kinase. Hyper-activated signaling through the ErbB-signaling network results in dysregulation of the cell cycle homeostatic machinery, with upregulation of active cyclin-D/CDK complexes. Recent data indicate that cell cycle regulators are also linked to chemoresistance in ErbB2-dependent breast carcinoma. Together with D-type cyclins, it seems that the CDK inhibitor p21 Waf1 plays an important role in evasion from apoptosis. These recent ®ndings herald a preliminary understanding of the output layer which connects elevated ErbB-signaling to oncogenesis and chemoresistance. Oncogene (2000) 19, 6102 ± 6114.

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Rac and Cdc42 Are Potent Stimulators of E2F-dependent Transcription Capable of Promoting Retinoblastoma Susceptibility Gene Product Hyperphosphorylation

Cited by 71 publications

References 52 publications

A Dual Role of the GTPase Rac in Cardiac Differentiation of Stem Cells

A Dual Role of the GTPase Rac in Cardiac Differentiation of Stem Cells

Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21CIP1 levels in androgen-independent human prostate cancer cells

Molecular mechanisms underlying ErbB2/HER2 action in breast cancer

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