PTENMMAC1TEP1 mutations in human primary renal‐cell carcinomas and renal carcinoma cell lines

Kondo, Keiichi; Yao, Masahiro; Kobayashi, Kazuki; Ota, S.; Yoshida, Minoru; Kaneko, Shotaro; M, Baba; Sakai, Naoki; Kishida, Takeshi; Kawakami, Satoshi; Uemura, Hiroji; Nagashima, Yoji; Nakatani, Yukio; Hosaka, Masahiko

doi:10.1002/1097-0215(200002)9999:9999<::aid-ijc1034>3.0.co;2-s

Cited by 82 publications

(47 citation statements)

References 24 publications

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“…This suggests that in this particular subgroup of cRCCs, inactivation of PTEN/MMAC1 may be involved in tumor progression. A recently published study of PTEN/MMAC1 mutations in renal cell carcinoma seems to support this conclusion, with four of five RCC patients (all with cRCC) with tumor PTEN/ MMAC1 mutations dying of their disease (16).…”

Section: Discussionmentioning

confidence: 88%

“…While Steck et al (11) reported mutations in one of four primary renal carcinomas, later, larger studies have found no, or very few, PTEN/MMAC1 mutations in RCC (13)(14)(15)(16)(17). Furthermore, observations in other human tumor types have also shown few PTEN/MMAC1 mutations despite high LOH rates at the gene locus (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, in the most recently published study of PTEN/MMAC1 mutations in RCC, at least two, and possibly three (as judged by the published sequencing gels), of the five tumors with PTEN/MMAC1 mutations appeared to have suffered heterozygote mutations. Nonetheless, only one of these individuals remained alive and free of disease (16).…”

Section: Discussionmentioning

confidence: 99%

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Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis

Velickovic¹,

Delahunt²,

McIver

et al. 2002

Modern Pathology

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As a group, renal epithelial malignancies are frequently encountered in clinical practice. It is now appreciated that rather than being a single tumor type, they consist of a variety of morphotypes that show differing clinical behavior (1-3). The most frequently encountered subtype is conventional (clear cell) renal cell carcinoma (cRCC), representing 70% of all adult malignant primary renal tumors, whereas papillary renal cell carcinoma (pRCC) account for 10 -15%, and chromophobe renal cell carcinoma (chRCC), for approximately 5%. The remainder is made up of collecting-duct carcinomas and unclassifiable tumors (2-5).

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis

Velickovic¹,

Delahunt²,

McIver

et al. 2002

Modern Pathology

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“…37,38 Reduced PTEN protein expression has been found in a high frequency in RCC and is associated with PKB/Akt activation in ccRCC, but interestingly not in pRCC. 2,39 The collected data suggests that in ccRCC the PTEN directed regulation of the PI-3 kinase pathway is affected by both genetic aberrations in the PTEN gene and by DJ-1 gene expression levels.…”

Section: Discussionmentioning

confidence: 99%

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

Sitaram

Cairney

Grabowski

et al. 2009

Intl Journal of Cancer

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DJ-1 is as a novel regulator of the tumor suppressor PTEN with stimulatory effects on PI3K-AKT/PKB signaling, one possible target of which is cMyc. The catalytic unit of the telomerase complex, hTERT, can be activated at different levels, including transcriptionally by cMyc and through phosphorylation by AKT/PKB. The aim of the study was to analyze the putative signaling pathway encompassing DJ-1, cMyc and hTERT in a series of 176 renal cell carcinomas (RCC) and experimentally in cell lines. DJ-1 mRNA expression was significantly elevated in clear cell RCC (ccRCC) compared with in papillary RCC (pRCC; p 5 0.005) and kidney cortex tissue (p < 0.001). ccRCC and pRCC demonstrated higher cMyc RNA levels than in kidney cortex (p < 0.001 for both) as well as increased levels of hTERT RNA (p < 0.001 and p 5 0.011, respectively). DJ-1 was positively correlated to cMyc and hTERT in ccRCC (p < 0.001 and p 5 0.019, respectively), but not in pRCC, indicating that this pathway could have a functional significance in ccRCC. siRNA knock down of DJ-1 induced downregulation of cMyc and hTERT mRNA associated with decreased expression of pAKT and cMyc protein levels. hTERT promoter activity was upregulated after DJ-1 transfection and this upregulation was inhibited after mutation of the cMyc binding sites. These experimental data support the functional link among DJ-1, cMyc and hTERT expression as indicated in the tumor material. Neither DJ-1, cMyc nor hTERT mRNA levels were associated with proliferation (S-phase fraction), telomere length or prognosis in ccRCC. ' UICCKey words: renal cell carcinoma; DJ-1; cMyc; hTERT; telomere length; proliferation; prognosis Renal cell carcinoma (RCC) constitutes a heterogeneous group of tumors regarding cytogenetic aberrations, morphologic appearance and clinical outcome. The WHO classification identifies different morphologic subtypes of sporadic RCC including the three most common types, clear cell (ccRCC), papillary (pRCC) and chromophobe RCC. 1 Each entity shows characteristic cytogenetic abnormalities indicating essential differences between the RCC subtypes regarding the mechanisms leading to tumor development.The phosphatase tensin homologue deleted on chromosome 10 (PTEN) protein is a well known tumor suppressor acting as a negative regulator of the phosphoinositide-3 (PI-3)-kinase pathway including the downstream Protein Kinase B (PKB)/Akt protein. In RCC, an association between decreased PTEN expression and high PKB/Akt activation has been described. 2 A novel protein, DJ-1 (also called Cap1/RS/PARK7), has been proposed to be involved in tumorigenesis by negatively regulating PTEN. 3 DJ-1 was first described as a protein showing a cooperative transforming activity with H-Ras in mouse NIH3T3 cells. 4 Overexpression of DJ-1 has been reported in several malignancies, including breast and lung. 5,6 Further, DJ-1 mRNA expression levels seemed to be associated with survival in lung cancer 3 and elevated levels of circulating DJ-1 and anti-DJ-1 auto-antibodies were detected in breast cance...

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“…PI3K signalling leads to phosphorylation and activation of AKT, which blocks apoptosis , promotes cytoplasmic sequestration of FoxO transcription factors (Brunet et al, 1999), and activates protein translation initiation via the mammalian target of rapamycin (mTOR) (Hay and Sonenberg, 2004). Phosphatase and tensin homolog (PTEN) mutations, which activate AKT, have been described in RCC in association with more aggressive disease (Kondo et al, 2001;Shin Lee et al, 2003). Mammalian target of rapamycin (mTOR) is inhibited by the tuberous sclerosis (TSC) complex, which, in turn, is inhibited by AKT and patients with TSC mutations have an increased incidence of RCC (Al-Saleem et al, 1998).…”

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confidence: 99%

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

et al. 2005

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Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFa) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel -Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHLdependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated posttranscriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation.

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PTENMMAC1TEP1 mutations in human primary renal‐cell carcinomas and renal carcinoma cell lines

Cited by 82 publications

References 24 publications

Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis

Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

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