Transcriptional basis of KRAS oncogene-mediated cellular transformation in ovarian epithelial cells

Tchernitsa, Oleg I.; Sers, Christine; Zuber, Johannes; Hinzmann, Bernd; Grips, Martin; Schramme, Anja; Lund, Per; Schwendel, Anke; Rosenthal, André; Schäfer, Reinhold

doi:10.1038/sj.onc.1207585

Cited by 70 publications

(71 citation statements)

References 76 publications

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“…However, blocking the ligand-activated EGF receptor signal transduction pathway by the specific EGF receptor inhibitor, tyrphostin AG1478, and the MEK inhibitor, PD098059, restored the normal level of Lot1 gene expression, indicating that the signaling from the EGF receptor to Lot1 expression is transmitted through MEK-ERK pathway. In agreement with these findings, another study reported that kRAS-induced transformation of ROSE cells downregulates Lot1, which is sensitive to the MEK inhibitor (Tchernitsa et al, 2004). The EGF effect was also confirmed in the human ovarian epithelial cells (Abdollahi et al, 2003).…”

Section: Role Of Growth Factor Signaling Pathwaysupporting

confidence: 76%

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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Lost-on-transformation 1 (LOT1) (PLAGL1/ZAC1) is a member of the novel subfamily of zinc-finger transcription factors, designated as PLAG family. The other members in this group include PLAG1 and PLAGL2, which share high homology with each other and with LOT1, particularly in their zinc-finger amino-terminal region. They are structurally similar but functionally different. For example, the LOT1 gene encodes a growth suppressor protein and is localized on human chromosome 6q24-25, a chromosomal region that is frequently deleted in many types of human cancers. The gene is maternally imprinted and is linked to developmental disorders such as growth retardation and transient neonatal diabetes mellitus (TNDM). LOT1 is a target of growth factor signaling pathway(s) and silenced by epigenetic mechanisms, as well as by the loss of heterozygosity in different tumor tissues. PLAG1 is a protooncogene that is localized on chromosome 8q12 and was found to be a target of several types of chromosomal rearrangement including the one identified in pleomorphic adenomas of the salivary gland. Since the discovery of the PLAG family members in 1997, much has been learned about their structure and function, as are summarized in this review. While the available data suggest that these proteins may play important roles in regulating normal physiological functions in the mammals, a great deal more about their signaling pathway(s), potential role in the complex pathologies such as cancer and developmental disorders, and functional relationship between different family members and splice variants still remains to be uncovered.

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Section: Role Of Growth Factor Signaling Pathwaysupporting

confidence: 76%

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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“…c-Fos expression in ovarian carcinoma S Mahner et al our study cannot determine whether the positive prognostic effect of c-Fos is the result of intrinsic differences in malignant potential of the tumours or of differences in chemo-resistance. Findings of previous experimental studies suggested that Fra-1 expression might also have a function in ovarian cancer (Hapke et al, 2003;Tchernitsa et al, 2004). However, our results could not show an impact of Fra-1, Fra-2 and FosB on ovarian cancer progression.…”

Section: Discussioncontrasting

confidence: 56%

C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma

et al. 2008

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Members of the Fos protein family dimerise with Jun proteins to form the AP-1 transcription factor complex. They have a central function in proliferation and differentiation of normal tissue as well as in oncogenic transformation and tumour progression. We analysed the expression of c-Fos, FosB, Fra-1 and Fra-2 to investigate the function of Fos transcription factors in ovarian cancer. A total of 101 patients were included in the study. Expression of Fos proteins was determined by western blot analysis, quantified by densitometry and verified by immunohistochemistry. Reduced c-Fos expression was independently associated with unfavourable progression-free survival (20.6, 31.6 and 51.2 months for patients with low, moderate and high c-Fos expression; P ¼ 0.003) as well as overall survival (23.8, 46.0 and 55.5 months for low, moderate and high c-Fos levels; P ¼ 0.003). No correlations were observed for FosB, Fra-1 and Fra-2. We conclude that loss of c-Fos expression is associated with tumour progression in ovarian carcinoma and that c-Fos may be a prognostic factor. These results are in contrast to the classic concept of c-Fos as an oncogene, but are supported by the recently discovered tumour-suppressing and proapoptotic function of c-Fos in various cancer types.

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“…Taken together with the observation that cells stably transformed with H-RAS or K-RAS oncogenes have increased levels of Fra-1 (43,44), our findings suggest that the MEK-ERK-Fra-1 pathway is a crucial pathway involved in both the initiation and maintenance of transformation by RAS oncogenes. …”

Section: Discussionmentioning

confidence: 73%

Oncogenic K-RAS Is Required to Maintain Changes in Cytoskeletal Organization, Adhesion, and Motility in Colon Cancer Cells

et al. 2005

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RAS oncogenes are thought to play a role at multiple stages of tumorigenesis. The role and mechanisms by which RAS oncogenes maintain the transformed state of human cancer cells are poorly understood. Here, we have studied the role of oncogenic K-RAS in maintaining cytoskeletal disruption, cell adhesion and motility in metastatic colon carcinoma cells. Targeted deletion of K-RAS G13D from HCT116 colon carcinoma cells restored their ability to assemble stress fibers and focal adhesions/complexes, accompanied by increased cell-matrix adhesion and reduced motility. We further show that oncogenic K-Ras induces high Rho activity, but uncouples Rho from stress fiber formation. This uncoupling required the maintenance of high levels of the activator protein-1 family member, Fra-1, via a mitogen-activated protein/extracellular signal-regulated kinase-dependent pathway. We also show that PI3-kinase signaling is required for the motility of HCT116 cells downstream of oncogenic K-Ras. Our findings suggest that mutated K-RAS oncogenes are essential for maintenance of the transformed and invasive phenotype of human colon cancer cells. (Cancer Res 2005; 65(4): 1244-50)

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Transcriptional basis of KRAS oncogene-mediated cellular transformation in ovarian epithelial cells

Cited by 70 publications

References 76 publications

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma

Oncogenic K-RAS Is Required to Maintain Changes in Cytoskeletal Organization, Adhesion, and Motility in Colon Cancer Cells

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