Transcriptional Signatures of Ral GTPase Are Associated with Aggressive Clinicopathologic Characteristics in Human Cancer

Smith, Steven C.; Baras, Alexander S.; Owens, Charles; Dancik, Garrett M.; Theodorescu, Dan

doi:10.1158/0008-5472.can-11-3966

Cited by 35 publications

(29 citation statements)

References 52 publications

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“…Anti-apoptotic NF-κB target genes such as Bcl-XL and the Bcl2 family member Bfl/A1 were also upregulated in DKO tumors but more modestly, which likely reflects a secondary effect of increased production of proinflammatory cytokines by DKO tumors (Figure S7A). While TNFα was increased in κB-Ras DKO tumors only, known Ral-dependent genes, such as MMP-1 (Smith et al, 2012) or CD24 (Smith et al, 2006), were upregulated in both κB-Ras deficient and Ral-GAPβ depleted tumors (Figure 6G, H and S7C). These results confirm that κB-Ras and Ral-GAP function through a common pathway and highlight that the regulation of NF-κB activity through κB-Ras proteins is independent of their effect on Ral-GAP/Ral activity.…”

Section: Resultsmentioning

confidence: 99%

κB-Ras Proteins Regulate Both NF-κB-Dependent Inflammation and Ral-Dependent Proliferation

et al. 2014

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Transformation of cells generally involves multiple genetic lesions that undermine control of both cell death and proliferation. We now report that κB-Ras proteins act as regulators of NF-κB and Ral pathways, which control inflammation/cell death and proliferation, respectively. Cells lacking κB-Ras therefore not only show increased NF-κB activity, that results in increased expression of inflammatory mediators, but also exhibit elevated Ral activity, that leads to enhanced anchorage-independent proliferation (AIP). κB-Ras deficiency consequently leads to significantly increased tumor growth that can be dampened by inhibiting either Ral or NF-κB pathways, revealing the unique tumor suppressive potential of κB-Ras proteins. Remarkably, numerous human tumors show reduced levels of κB-Ras, and increasing the level of κB-Ras in these tumor cells impairs their ability to undergo AIP, thereby implicating κB-Ras proteins in human disease.

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Section: Resultsmentioning

confidence: 99%

κB-Ras Proteins Regulate Both NF-κB-Dependent Inflammation and Ral-Dependent Proliferation

et al. 2014

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“…The phosphorylation of RALB at S198 by protein kinase C (PKC) is an important driver of bladder cancer growth and metastasis via promotion of the RALB-RALBP1 interaction [65] . A transcriptional signature was recently developed to report cellular RAL activity levels [74] . This RAL signature was predictive of cancer patient outcomes, indicating for the first time that the genes and pathways regulated by RAL are important for tumor formation and progression in cancer patients [74] .…”

Section: Ral In Cancermentioning

confidence: 99%

“…A transcriptional signature was recently developed to report cellular RAL activity levels [74] . This RAL signature was predictive of cancer patient outcomes, indicating for the first time that the genes and pathways regulated by RAL are important for tumor formation and progression in cancer patients [74] .…”

Section: Ral In Cancermentioning

confidence: 99%

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Guin

Theodorescu

2015

Acta Pharmacol Sin

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Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer. Review RAS GTPase overviewRAS is the most extensively studied GTPase [1] . It is known to regulate various cellular functions, including proliferation, survival, growth, migration, differentiation and cytoskeletal dynamics [2][3][4] (Figure 1). Not coincidentally, increased activities of all of these processes are required by tumor cells to promote tumor growth. Activating oncogenic RAS mutations lead to treatment resistance in various tumor models and poor patient outcomes [3,[5][6][7][8][9] . Three human RAS genes have been identified: HRAS, KRAS, and NRAS [1,2] . These encode the related proteins HRAS, KRAS and NRAS, respectively, of 189 amino acids in length [1,4] . KRAS exists as two isoforms, 4A and 4B, which are generated by alternative exon splicing [10] . These different RAS genes are well known to have differential cellular specificities and intrinsic transforming potentials [3,4,10] .In normal cells, RAS proteins act as molecular switches for critical cellular functions. RAS proteins are activated by upstream receptors such as receptor tyrosine kinases * To whom correspondence should be addressed. E-mail dan.theodorescu@ucdenver.edu Received 2014-08-07 Accepted 2014-10-30 Figure 1. RAS GTPase activation and downstream signaling. The cartoon shows the mechanism of RAS GTPase activation by upstream stimuli and numerous downstream effectors stimulated by activated RAS. RAS regulates critical cellular functions through these effectors. Constitutive RAS activation due to mutations leads to protumorigenic signaling through these effectors.

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“…While Ral mutations are not commonly found in these tumors, higher than normal Ral activity has been shown to result from a number of different mechanisms, including the loss of microRNA mediated inhibition [28], increased GEF expression [29], and decreased GAP activity [30]. The level of Ral activity, as measured by comparison to a transcriptional signature of Ral-dependent genes, correlates positively with a number of poor prognostic factors, including disease stage, progression to muscle invasion and survival in bladder cancer, and seminal vesicle invasion and androgen-independent progression in prostate cancer [31]. Collectively, these studies highlight the need to better understand how RalA and RalB signal to their downstream effectors to promote tumorigenic processes and to continue to lift the RalGEF-Ral pathway out of the shadow of the more intensely-studied and better-understood MAP kinase and PI3K pathways.…”

Section: Introductionmentioning

confidence: 99%

Ral GTPases in tumorigenesis: Emerging from the shadows

Kashatus¹

2013

Experimental Cell Research

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Oncogenic Ras proteins rely on a series of key effector pathways to drive the physiological changes that lead to tumorigenic growth. Of these effector pathways, the RalGEF pathway, which activates the two Ras-related GTPases RalA and RalB, remains the most poorly understood. This review will focus on key developments in our understanding of Ral biology, and will speculate on how aberrant activation of the multiple diverse Ral effector proteins might collectively contribute to oncogenic transformation and other aspects of tumor progression.

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Transcriptional Signatures of Ral GTPase Are Associated with Aggressive Clinicopathologic Characteristics in Human Cancer

Cited by 35 publications

References 52 publications

κB-Ras Proteins Regulate Both NF-κB-Dependent Inflammation and Ral-Dependent Proliferation

κB-Ras Proteins Regulate Both NF-κB-Dependent Inflammation and Ral-Dependent Proliferation

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Ral GTPases in tumorigenesis: Emerging from the shadows

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