The Kinase Mirk/Dyrk1b Mediates Cell Survival in Pancreatic Ductal Adenocarcinoma

Deng, Xiaobing; Li, S; Naqvi, Ahmad Abu Turab; Friedman, Eileen

doi:10.1097/01.mpa.0000193657.79030.64

Cited by 10 publications

(28 citation statements)

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“…High level Mirk protein levels were seen in Panc1 and SU86.86 cells (ref. 3; HPAC not tested), which is consistent with the Mirk gene residing within this amplicon. In a recent report (3), Mirk was shown to have a major role in mediating the survival of clonogenic pancreatic cancers.…”

Section: Introductionmentioning

confidence: 55%

“…3; HPAC not tested), which is consistent with the Mirk gene residing within this amplicon. In a recent report (3), Mirk was shown to have a major role in mediating the survival of clonogenic pancreatic cancers. Mirk was expressed in the majority (89%) of resected pancreatic cancers, with elevated expression in 39%, and in the developing ductal epithelium of each of five fetal pancreases.…”

Section: Introductionmentioning

confidence: 55%

“…Colony formation assays test for the most aggressive cells within a tumor cell line. In earlier studies, our group had shown that depletion of Mirk from Panc1 cells by a plasmid-based RNAi vector decreased anchorage-dependent colony formation by 3-to 5-fold, whereas depletion of Mirk by two different RNAi duplex oligonucleotides induced apoptosis in Panc1 and two other pancreatic cancer cell lines (3). Apoptosis of the clonogenic cancer cells following loss of Mirk thus seemed to be responsible for the decrease in clonogenicity.…”

Section: Resultsmentioning

confidence: 99%

“…The K-ras2G12V, K-ras2S17N, and H-rasG12V expression plasmids were from the UMR cDNA Resource Center (Rolla, MO). All other plasmids have been described previously (3)(4)(5)(6).…”

Section: Methodsmentioning

confidence: 99%

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The Survival Kinase Mirk/Dyrk1B Is a Downstream Effector of Oncogenic K-ras in Pancreatic Cancer

et al. 2007

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The kinase Mirk is overexpressed in many resected pancreatic adenocarcinomas and is amplified in a subset of pancreatic cancer cell lines. Depletion of Mirk has been shown to lead to apoptosis in pancreatic cancer cell lines, and thus to inhibit their clonogenic growth. Mirk is activated by signaling from activated Rac1 to MKK3 in MDCK cells, but the mechanism of activation of Mirk in pancreatic cancers is unknown. In this report, Mirk is shown to be a novel effector of K-ras, a gene mutated in f90% of pancreatic cancers. Activation of Mirk signaling from oncogenic K-ras through Rac1 was shown in transient expression systems and reporter assays. Mirk activation in pancreatic cancer cells was blocked by RNA interference using three different synthetic duplex RNAis to K-ras, or two RNAis to Rac1, by pharmacologic inhibition of Rac1, or by expression of dominant negative K-rasS17N. Rac1 was activated in four out of five pancreatic cancer cell lines, and was activated by signaling from oncogenic K-ras. Mirk knockout does not induce embryonic lethality, and depletion of Mirk had no effect on the survival of normal diploid fibroblasts. In contrast, the clonogenic ability of Panc1 and AsPc1 pancreatic cancer cell lines was reduced 8-to 12-fold by the depletion of Mirk, with a greater reduction seen following the depletion of K-ras or both genes. Mirk is a novel downstream effector of oncogenic K-ras and mediates some of the survival signals activated by ras signaling. [Cancer Res 2007;67(15):7247-55]

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Section: Introductionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 99%

“…The K-ras2G12V, K-ras2S17N, and H-rasG12V expression plasmids were from the UMR cDNA Resource Center (Rolla, MO). All other plasmids have been described previously (3)(4)(5)(6).…”

Section: Methodsmentioning

confidence: 99%

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The Survival Kinase Mirk/Dyrk1B Is a Downstream Effector of Oncogenic K-ras in Pancreatic Cancer

et al. 2007

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“…These findings indicate that AKT2 is clearly not the main target of the 19q13 amplification in pancreatic cancer although it cannot be ruled out that simultaneous activation of AKT2 with other candidate genes from this region might provide a growth advantage for the cancer cells. Recently, two other genes from this region, PAF1 and DYRK1B, were proposed to associate with pancreatic cancer development and cell survival, respectively (35,36). Yet, again, our data do not show evidence that these genes would be the key targets of 19q13 amplicon.…”

Section: Discussionmentioning

confidence: 99%

Intersex-like (IXL) Is a Cell Survival Regulator in Pancreatic Cancer with 19q13 Amplification

et al. 2007

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Pancreatic cancer is a highly aggressive disease characterized by poor prognosis and vast genetic instability. Recent microarray-based, genome-wide surveys have identified multiple recurrent copy number aberrations in pancreatic cancer; however, the target genes are, for the most part, unknown. Here, we characterized the 19q13 amplicon in pancreatic cancer to identify putative new drug targets. Copy number increases at 19q13 were quantitated in 16 pancreatic cancer cell lines and 31 primary tumors by fluorescence in situ hybridization. Cell line copy number data delineated a 1.1 Mb amplicon, the presence of which was also validated in 10% of primary pancreatic tumors. Comprehensive expression analysis by quantitative real-time reverse transcription-PCR indicated that seven transcripts within this region had consistently elevated expression levels in the amplified versus nonamplified cell lines. High-throughput loss-of-function screen by RNA interference was applied across the amplicon to identify genes whose down-regulation affected cell viability. This screen revealed five genes whose down-regulation led to significantly decreased cell viability in the amplified PANC-1 cells but not in the nonamplified MiaPaca-2 cells, suggesting the presence of multiple biologically interesting genes in this region. Of these, the transcriptional regulator intersex-like (IXL) was consistently overexpressed in amplified cells and had the most dramatic effect on cell viability. IXL silencing also resulted in G 0 -G 1 cell cycle arrest and increased apoptosis in PANC-1 cells. These findings implicate IXL as a novel amplification target gene in pancreatic cancer and suggest that IXL is required for cancer cell survival in 19q13-amplified tumors. [Cancer Res 2007;67(5):1943-9]

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Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/Rb2

Nakhla

Friedman

2010

Intl Journal of Cancer

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Some ovarian cancer cells in vivo are in a reversible quiescent state where they can contribute to cancer spread under favorable growth conditions. The serine/threonine kinase Mirk/dyrk1B was expressed in each of seven ovarian cancer cell lines and in 21 of 28 resected human ovarian cancers, and upregulated in 60% of the cancers. Some ovarian cancer cells were found in a G0 quiescent state, with the highest fraction in a line with an amplified Mirk gene. Suboptimal culture conditions increased the G0 fraction in SKOV3 and TOV21G, but not OVCAR4 cultures. Less than half as many OVCAR4 cells survived under suboptimal culture conditions as shown by total cell numbers, dye exclusion viability studies, and assay of cleaved apoptotic marker proteins. G0 arrest in TOV21G and SKOV3 cells led to increased levels of Mirk, the CDK inhibitor p27, p130/Rb2, and p130/Rb2 complexed with E2F4. The G0 arrest was transient, and cells exited G0 when fresh nutrients were supplied. Depletion of p130/Rb2 reduced the G0 fraction, increased cell sensitivity to serum-free culture and to cisplatin, and reduced Mirk levels. Mirk contributed to G0 arrest by destabilization of cyclin D1. In TOV21G cells, but not in normal diploid fibroblasts, Mirk depletion led to increased apoptosis and loss of viability. Because Mirk is expressed at low levels in most normal adult tissues, the elevated Mirk protein levels in ovarian cancers may present a novel therapeutic target, in particular for quiescent tumor cells which are difficult to eradicate by conventional therapies targeting dividing cells.Normal diploid cells such as lymphocytes and fibroblasts go into a reversible growth arrest called quiescence in response to anti-proliferative environmental signals. These normal cells maintain quiescence through upregulating the CDK inhibitor p27 in part through increasing the stability of the CDK inhibitor p27 through the kinase Mirk, 1-3 upregulate the transcriptional repressor HES1 to block senescence or differentiation, 4,5 and block apoptosis through several mechanisms. A subpopulation of tumor cells, possibly including stem cells, remains in a nondividing quiescent state that renders them relatively resistant to chemotherapy and radiation therapy which target dividing cells.6 By entering a quiescent state, tumor cells can resist the nutrient deficiencies, hypoxic and acidic conditions within the tumor mass. Mirk has also been reported by our group to maintain the viability of quiescent pancreatic cancer cells by reducing intracellular levels of reactive oxygen species (ROS). 7 Normal cells in quiescence activate pathways that protect them from metabolic stress, and a subpopulation of tumor cells is likely to utilize similar pathways to survive within the tumor microenvironment. The anti-apoptotic proteins BCL2 and BCL-XL have been shown to facilitate G0 quiescence in murine embryonic fibroblasts by decreasing RNA content and cell size, and by upregulating p27 protein through its stabilization following phosphorylation of p27Ser10 by Mirk. 3 Epit...

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The Kinase Mirk/Dyrk1b Mediates Cell Survival in Pancreatic Ductal Adenocarcinoma

Cited by 10 publications

References 0 publications

The Survival Kinase Mirk/Dyrk1B Is a Downstream Effector of Oncogenic K-ras in Pancreatic Cancer

The Survival Kinase Mirk/Dyrk1B Is a Downstream Effector of Oncogenic K-ras in Pancreatic Cancer

Intersex-like (IXL) Is a Cell Survival Regulator in Pancreatic Cancer with 19q13 Amplification

Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/Rb2

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