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Isolation of ORCTL3 in a novel genetic screen for tumor-specific apoptosis inducers.

Irshad S, Mahul-Mellier AL, Kassouf N, Lemarie A, Grimm S - Cell Death Differ. (2009)

Bottom Line: Although ORCTL3 is a member of the organic cation transporter gene family, our data indicate that this gene induces apoptosis independently of its putative transporter activity.Rather, various lines of evidence suggest that ORCTL3 brings about apoptosis by an endoplasmic reticulum stress-mediated mechanism.Finally, we detected ORCTL3 to be downregulated in human kidney tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine and Toxicology, Imperial College London, Hammersmith Campus, London, UK.

ABSTRACT
We have established a systematic high-throughput screen for genes that cause cell death specifically in transformed tumor cells. In a first round of screening, cDNAs that induce apoptosis in a transformed human cell line are detected. Positive genes are subsequently tested in a synthetic lethal screen in normal cells versus their isogenic counterparts that have been transformed by a particular oncogene. In this way, the organic cation transporter-like 3 (ORCTL3) gene was found to be inactive in normal rat kidney (NRK) cells, but to induce apoptosis in NRK cells transformed by oncogenic H-ras. ORCTL3 also causes cell death in v-src-transformed cells and in various human tumor cell lines but not in normal cells or untransformed cell lines. Although ORCTL3 is a member of the organic cation transporter gene family, our data indicate that this gene induces apoptosis independently of its putative transporter activity. Rather, various lines of evidence suggest that ORCTL3 brings about apoptosis by an endoplasmic reticulum stress-mediated mechanism. Finally, we detected ORCTL3 to be downregulated in human kidney tumors.

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ORCTL3 is downregulated in human renal tumors. A commercial filter blot (Cancer Profiling Array, Clontech) with matched RNA of tumor and normal tissue from each patient was probed with ORCTL3. The signal intensities were measured with densitometry and the %-values of the tumor signals relative to the normal tissues were calculated for each patient and plotted (p<0.01, n=20). No signals were detected in other tissues, most likely due to reduced expression levels.
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Figure 7: ORCTL3 is downregulated in human renal tumors. A commercial filter blot (Cancer Profiling Array, Clontech) with matched RNA of tumor and normal tissue from each patient was probed with ORCTL3. The signal intensities were measured with densitometry and the %-values of the tumor signals relative to the normal tissues were calculated for each patient and plotted (p<0.01, n=20). No signals were detected in other tissues, most likely due to reduced expression levels.

Mentions: A broader role of ORCTL3 during tumorigenesis was suggested as deletions in its chromosomal locus 3p21.3 have been linked to carcinomas of various organs (25, 26). We found microarray data with significant p-values from the Oncomine database indicating that this gene is repressed in tumors of the adrenal gland and the bladder (not shown). Importantly, using the Cancer Profiling Array, a blot that compares tumor versus normal tissue of the same patients, we detected that ORCTL3 is significantly downregulated in human renal carcinomas (Fig. 7).


Isolation of ORCTL3 in a novel genetic screen for tumor-specific apoptosis inducers.

Irshad S, Mahul-Mellier AL, Kassouf N, Lemarie A, Grimm S - Cell Death Differ. (2009)

ORCTL3 is downregulated in human renal tumors. A commercial filter blot (Cancer Profiling Array, Clontech) with matched RNA of tumor and normal tissue from each patient was probed with ORCTL3. The signal intensities were measured with densitometry and the %-values of the tumor signals relative to the normal tissues were calculated for each patient and plotted (p<0.01, n=20). No signals were detected in other tissues, most likely due to reduced expression levels.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2683172&req=5

Figure 7: ORCTL3 is downregulated in human renal tumors. A commercial filter blot (Cancer Profiling Array, Clontech) with matched RNA of tumor and normal tissue from each patient was probed with ORCTL3. The signal intensities were measured with densitometry and the %-values of the tumor signals relative to the normal tissues were calculated for each patient and plotted (p<0.01, n=20). No signals were detected in other tissues, most likely due to reduced expression levels.
Mentions: A broader role of ORCTL3 during tumorigenesis was suggested as deletions in its chromosomal locus 3p21.3 have been linked to carcinomas of various organs (25, 26). We found microarray data with significant p-values from the Oncomine database indicating that this gene is repressed in tumors of the adrenal gland and the bladder (not shown). Importantly, using the Cancer Profiling Array, a blot that compares tumor versus normal tissue of the same patients, we detected that ORCTL3 is significantly downregulated in human renal carcinomas (Fig. 7).

Bottom Line: Although ORCTL3 is a member of the organic cation transporter gene family, our data indicate that this gene induces apoptosis independently of its putative transporter activity.Rather, various lines of evidence suggest that ORCTL3 brings about apoptosis by an endoplasmic reticulum stress-mediated mechanism.Finally, we detected ORCTL3 to be downregulated in human kidney tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine and Toxicology, Imperial College London, Hammersmith Campus, London, UK.

ABSTRACT
We have established a systematic high-throughput screen for genes that cause cell death specifically in transformed tumor cells. In a first round of screening, cDNAs that induce apoptosis in a transformed human cell line are detected. Positive genes are subsequently tested in a synthetic lethal screen in normal cells versus their isogenic counterparts that have been transformed by a particular oncogene. In this way, the organic cation transporter-like 3 (ORCTL3) gene was found to be inactive in normal rat kidney (NRK) cells, but to induce apoptosis in NRK cells transformed by oncogenic H-ras. ORCTL3 also causes cell death in v-src-transformed cells and in various human tumor cell lines but not in normal cells or untransformed cell lines. Although ORCTL3 is a member of the organic cation transporter gene family, our data indicate that this gene induces apoptosis independently of its putative transporter activity. Rather, various lines of evidence suggest that ORCTL3 brings about apoptosis by an endoplasmic reticulum stress-mediated mechanism. Finally, we detected ORCTL3 to be downregulated in human kidney tumors.

Show MeSH
Related in: MedlinePlus