K-ras modulates the cell cycle via both positive and negative regulatory pathways

Fan, Jun‐Yu; Bertino, Joseph R.

doi:10.1038/sj.onc.1201105

Cited by 66 publications

(39 citation statements)

References 48 publications

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“…Since the phenotypes of RacV12 expression and E2F overexpression are similar, notably anchorage-independent growth and enhanced saturation density (5,7,40), we suggest that E2F stimulation contributes to the oncogenic potential of activated Rac. The ability of activated Rac and Cdc42 to up-regulate E2F transcriptional activity is consistent with published reports for the related small GTPase Ras, which, in its oncogenic form, also induces E2F-dependent transcription (41,42) (Fig. 1).…”

Section: Discussionsupporting

confidence: 90%

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

Gjoerup

Lukáš

Bártek

et al. 1998

Journal of Biological Chemistry

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The Rho family of GTPases plays an important and diverse role in reorganization of the actin cytoskeleton, transcriptional regulation, and multiple aspects of cell growth. Our study has examined their potential links to the cell cycle machinery. We find that constitutively active mutants of Rac and Cdc42, but not Rho, are potent inducers of E2F transcriptional activity in NIH 3T3 fibroblasts. Furthermore, activated Rac and Cdc42, but again not Rho, are capable of inducing cyclin D1 accumulation and pRB hyperphosphorylation in serum-deprived cells, outlining one route leading to enhanced E2F-mediated transcription. The inhibitory effect of the cyclin-dependent kinase inhibitors, p16 ink4 , p21cip1 , and p27 cip on Rac/Cdc42-mediated E2F transcription corroborates a role for pRB family members and their functional inactivation by cyclin-dependent kinases in generating E2F activity. While the up-regulation of E2F transcriptional activity by Rac or Cdc42, not Rho, suffices for entry into S phase and DNA synthesis in Rat-1 R12 cells, this is clearly not the case in NIH 3T3, where additional requirements must exist.

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Section: Discussionsupporting

confidence: 90%

“…1). For Ras it is generally assumed that a significant contribution to its mitogenic potential comes from its ability to transcriptionally up-regulate cyclin D1 (34,35,41,(43)(44)(45). Ectopic expression of cyclin D1 accelerates G 1 progression (46), and it bypasses the need for Ras in proliferation of exponentially growing fibroblasts (47).…”

Section: Discussionmentioning

confidence: 99%

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

Gjoerup

Lukáš

Bártek

et al. 1998

Journal of Biological Chemistry

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“…An activated K-RAS has been reported to modulate cycling cells through a wide spectrum of cell cycle regulators (30), but in particular, facilitates transition from G 2 -M into the next cycle (31). Our findings with Internavec were consistent with cell cycle blockage events that resulted from early viral gene expression as well as K-ras knockdown, culminating in S and G 2 -M phase arrests.…”

Section: Resultssupporting

confidence: 83%

Antitumor Activity of an Oncolytic Adenovirus-Delivered Oncogene Small Interfering RNA

et al. 2006

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Despite successes in animal models, cancer gene therapy with small interfering RNAs (siRNA) is hindered by the lack of an optimal delivery platform. We examined the applicability of the replication-competent, oncolytic adenovirus, ONYX-411, to deliver a mutant K-ras siRNA transgene to human cancer cells. Proof-of-principle studies showed an additive tumor growth-inhibitory response through siRNA-mediated K-ras knockdown and ONYX-411-mediated cancer cell lysis. A novel construct, termed Internavec ( for interfering RNA vector), was generated by cloning a K-ras v12 -specific siRNA ras-4 hairpin construct under the control of the human H1 promoter into the deleted E3b region of ONYX-411. Internavec acquired an increase in potency of f10-fold in human cancer cells expressing the relevant K-ras v12 mutation (H79, H441, and SW480), as defined by a reduction in the effective dose needed to achieve 50% growth inhibition (ED 50 ). Internavec remained attenuated in nonmalignant epithelial cells. Daily intratumoral injections of Internavec ( five daily injections of 1 Â 10 8 plaque-forming units) significantly reduced the growth of s.c. H79 pancreatic cancer xenografts in nu/nu mice by 85.5%, including complete growth suppression in three of five mice. Parental ONYX-411 or ONYX-411-siRNA GFP was markedly less effective (47.8% growth reduction, P = 0.03; and 44.1% growth reduction, P = 0.03, respectively). siRNA ras transgene activity contributed to cell cycle blockage, increased apoptosis, and marked down-regulation of Ras signaling-related gene expression (AKT2, GSK3b, E2F2, and MAP4K5 ). These findings indicate that Internavec can generate a two-pronged attack on tumor cells through oncogene knockdown and viral oncolysis, resulting in a significantly enhanced antitumor outcome.

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“…24,25). These genes are associated with mitotic cell cycle, M phase, and cell proliferation, and the expression of some of them is reportedly controlled by Ras (25,26). Here, too, EXPANDER identified other genes that could represent novel putative NF-Y targets.…”

Section: Cancer Researchmentioning

confidence: 89%

Gene Expression Signature of Human Cancer Cell Lines Treated with the Ras Inhibitor Salirasib (S-Farnesylthiosalicylic Acid)

Blum¹,

Elkon²,

Yaari³

et al. 2007

Cancer Research

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K-ras modulates the cell cycle via both positive and negative regulatory pathways

Cited by 66 publications

References 48 publications

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

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

Antitumor Activity of an Oncolytic Adenovirus-Delivered Oncogene Small Interfering RNA

Gene Expression Signature of Human Cancer Cell Lines Treated with the Ras Inhibitor Salirasib (S-Farnesylthiosalicylic Acid)

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