Functional Identification of Tumor-Suppressor Genes through an In Vivo RNA Interference Screen in a Mouse Lymphoma Model

Bric, Anka; Miething, Cornelius; Bialucha, Carl U.; Scuoppo, Claudio; Zender, Lars; Krasnitz, Alexander; Xuan, Zhenyu; Zuber, Johannes; Wigler, Michael; Hicks, James; McCombie, W. Richard; Hemann, Michael T.; Hannon, Gregory J.; Powers, Scott; Lowe, Scott W.

doi:10.1016/j.ccr.2009.08.015

Cited by 157 publications

(127 citation statements)

References 52 publications

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“…37 Although deletion of Mek1 inhibits tumor formation in the skin, 38 it was shown that shRNA knockdown of Mek1 in murine hematopoietic stem cells facilitated Myc-induced tumor development. 39 However, the decrease in survival of the mice with Mek1 knockdown was not reported to be statistically significant, but may reflect different requirements of Mek1 signaling in stem cells. Recently, a pharmacological MEK inhibitor was shown to kill human diffuse large B-cell lymphoma cells, which frequently overexpress Myc.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis

Gramling

Eischen

2012

Cell Death Differ

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Although the Myc transcription factor has been shown necessary for the oncogenic function of Ras, the contribution of Ras pathway signaling to the oncogenic function of Myc remains unresolved. We report the novel findings that Myc alone induced Ras/Mapk pathway signaling, and increased signaling following growth factor stimulation. Deletion of the scaffold protein kinase suppressor of Ras 1 (Ksr1) attenuated signaling through the Ras/Mapk pathway, including activation following Myc induction. B cells that lacked Ksr1 exhibited reduced proliferation and increased cytokine deprivation-induced apoptosis. Overexpression of Myc rescued the proliferation defect of Ksr1-null B cells, but loss of Ksr1 increased sensitivity of B cells to Myc-induced apoptosis. Notably, there was a significant delay in lymphoma development in Ksr1-null mice overexpressing Myc in B cells (El-myc transgenic mice). There was an elevated frequency of p53 inactivation, indicative of increased selective pressure to bypass the p53 tumor suppressor pathway, in Ksr1-null El-myc lymphomas. Therefore, loss of Ksr1 inhibits Ras/Mapk pathway signaling leading to increased Myc-induced B-cell apoptosis, and this results in reduced B-cell transformation and lymphoma development. The c-Myc transcription factor is an oncoprotein that is frequently overexpressed in hematological malignancies through translocations, amplifications, and other less characterized mechanisms. Overexpression of Myc, which drives cell cycle progression, is a well-characterized initiating step in human Burkitt's lymphoma, a non-Hodgkin's B-cell lymphoma. The role of Myc in non-Hodgkin's B-cell lymphoma was established in part by the Em-myc transgenic mouse model that overexpresses Myc in B-cells and develops pre-B/B-cell lymphoma. 1 Overexpression of Myc in primary B cells triggers activation of the Arf-Mdm2-p53 tumor suppressor pathway, which leads to apoptosis. Specifically, Myc induces Arf, which inhibits Mdm2, causing p53 activation and B-cell apoptosis. Myc-overexpressing B cells that acquire mutations that inhibit apoptosis survive and can be transformed. This is exemplified in that 80% of the lymphomas that arise in Em-myc mice have deleted Arf, overexpress Mdm2, or have mutated or deleted p53, all of which inhibit Myc-induced apoptosis. 2 Similar observations have been made in human lymphomas. [3][4][5] Therefore, whereas Myc overexpression induces B-cell transformation in vivo, it requires B cells to gain resistance to apoptosis induced by the hyperproliferative signals from Myc for this to occur.The Ras-Raf-Mek-Mapk/Erk (Ras/Mapk) signaling pathway is essential for cell growth, differentiation, and cell survival. 6 Kinase suppressor of Ras 1 (Ksr1) was first identified as a positive modulator of Ras signaling in genetic screens of Drosophila and C. elegans. 7 Subsequent studies have shown Ksr1 functions as a scaffold protein that can bind and facilitate signaling of multiple components of the Ras/Mapk signaling pathway. 6 Deletion of Ksr1 results in decreased Mapk-Erk1/2 ...

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Section: Discussionmentioning

confidence: 99%

Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis

Gramling

Eischen

2012

Cell Death Differ

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“…For the in vivo screen, we employed the Cancer 1000 shRNA library consisting of 2,204 shRNAs, targeting a panel of about 1,000 cancer-associated mouse genes (8,23), with a subpool complexity of 96 shRNAs (24 subpools). The screen strategy is outlined in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, such screens are unable to differentiate the mechanisms of greatest clinical relevance and may miss additional in vivo-specific drivers of response and resistance (6,7). In vivo RNAi screening has emerged as a physiologically relevant approach to explore gene function in tumor biology (8)(9)(10) and therapeutic response (11). In this study, we have adapted an in vivo short-hairpin (sh)RNAi approach combined with massively parallel sequencing to reveal novel determinants of response to anthracycline chemotherapy in a model of breast cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Ashenden

Weverwijk

Murugaesu

et al. 2017

Molecular Cancer Therapeutics

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Chemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of firstline chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK inhibition both promotes tumor cell cytostasis and blocks activation of the proapoptotic protein Bax, thereby antagonizing chemotherapy-mediated cytotoxicity. To investigate the clinical relevance of this dual role of JNK signaling, we developed a proliferation-independent JNK activity signature and demonstrate high JNK activity to be enriched in triple-negative and basal-like breast cancer subtypes. Consistent with the dual role of JNK signaling in vitro, high-level JNK pathway activation in triplenegative breast cancers is associated both with poor patient outcome in the absence of chemotherapy treatment and, in neoadjuvant clinical studies, is predictive of enhanced chemotherapy response. These data highlight the potential of monitoring JNK activity as early biomarker of response to chemotherapy and emphasize the importance of rational treatment regimes, particularly when combining cytostatic and chemotherapeutic agents.

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“…There have been many studies demonstrated that inhibition of ATR-Chk1 signalling cascades promotes tumourigenesis in select cancer cell lines (Bric et al, 2009;Fang et al, 2004). Therefore, the potential side effect that the secondary cancers arise due to Chk1 suppression needs more investigation (Tse et al, 2007a (Curtin, 2012).…”

Section: Figure16 Schematic Representation Of the Effect Of Chk1 Onmentioning

confidence: 99%

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

2014

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Functional Identification of Tumor-Suppressor Genes through an In Vivo RNA Interference Screen in a Mouse Lymphoma Model

Cited by 157 publications

References 52 publications

Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis

Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

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