The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation.

Recent genetic studies have documented a pivotal growth-regulatory role played by the Cullin 7 (CUL7) E3 ubiquitin ligase complex containing the Fbw8-substrate-targeting subunit, Skp1, and the ROC1 RING finger protein. In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities. Interestingly, while embryonic fibroblasts of Cul7-/- mice were found to accumulate IRS-1 and exhibit increased activation of IRS-1's downstream Akt and MEK/ERK pathways, these null cells grew poorly and displayed phenotypes reminiscent of those associated with oncogene-induced senescence. Taken together, our findings demonstrate a key role for the CUL7 E3 in targeting IRS-1 for degradation, a process that may contribute to the regulation of cellular senescence.

Expression of a mutant p193/CUL7 molecule confers resistance to MG132- and etoposide-induced apoptosis independent of p53 or Parc binding.

p193/CUL7 is an E3 ubiquitin ligase initially identified as an SV40 Large T Antigen binding protein. Expression of a dominant interfering variant of mouse p193/CUL7 (designated 1152stop) conferred resistance to MG132- and etoposide-induced apoptosis in U2OS cells. Immune precipitation/Western analyses revealed that endogenous p193/CUL7 formed a complex with Parc (a recently identified parkin-like ubiquitin ligase) and p53. Apoptosis resistance did not result from 1152stop-mediated disruption of the endogenous p193/CUL7 binding partners. Moreover, 1152stop molecule did not directly bind to endogenous p193/CUL7, Parc or p53. These data suggested a role for p193/CUL7 in the regulation of apoptosis independently of p53 and Parc activity.

Decreased survival in EGFR gene amplified vulvar carcinoma.

OBJECTIVE: We undertook an extensive molecular characterization of the epidermal growth factor receptor (EGFR) gene in vulvar squamous cell carcinomas to investigate EGFR mutation and/or genomic amplification and its association with EGFR protein expression, high-risk human papillomavirus (HPV) status and clinical outcome. METHODS: A cohort of 51 vulvar cancer patients distributed across all FIGO stages was selected for immunohistochemistry (IHC) and fluorescence in situ hybridization. EGFR expression and gene amplification were correlated with high-risk HPV status, EGFR mutational status and clinical prognostic variables. Fisher's exact tests, Kaplan-Meier survival estimates and a Cox proportional-hazards model were utilized. RESULTS: EGFR gene amplification and chromosome 7 high polysomy were observed in 12% and 6% of cases, respectively. IHC of malignant tissue with 3+ staining demonstrated 100% sensitivity and 79% specificity to detect EGFR gene amplification, yielding a 39% positive predictive value. Decreased survival (p<0.025) was observed in patients with gene amplification, and was associated with a more statistically robust 3.3 hazard ratio (p<0.005) in the Cox proportional-hazards model that controlled for age at diagnosis, stage and lymph node metastasis. Univariate analysis confirmed that EGFR gene amplification was associated with the absence of high-risk HPV (p<0.001). Common activating EGFR gene mutations were not identified. CONCLUSION: A subset of patients with vulvar squamous cell carcinoma was identified with EGFR gene amplification that was HPV-independent and associated with poor prognosis. Given the association of EGFR amplification with response to targeted therapy in other tumor types, these patients may be candidates for therapeutic strategies that target the EGFR pathway.

Unusual tumor response and toxicity from radiation and concurrent erlotinib for non-small-cell lung cancer.

We report a case of a never-smoker female with non-small-cell lung cancer (NSCLC) who experienced a striking tumor response to combined low-dose radiation and the epidermal growth factor receptor inhibitor erlotinib, even though erlotinib alone was not effective in preventing tumor progression. Furthermore, the patient developed symptomatic pneumonitis, which is unusual for the small volume of lung that was exposed to a significant dose of radiation. This case demonstrates that combination therapy with radiation and erlotinib has the potential to significantly benefit a subset of patients with NSCLC in addition to those approximately 10% who have tumors which respond to erlotinib alone. It also highlights the potential risks of molecular targeted radiation therapy.

Uterine tumors resembling ovarian sex cord tumors (UTROSCT) lack the JAZF1-JJAZ1 translocation frequently seen in endometrial stromal tumors.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare uterine neoplasm composed predominantly or exclusively of cells which resemble those seen in sex cord tumors of the ovary. Since its initial morphologic description, it has been unclear whether UTROSCT represents a variant within the spectrum of endometrial stromal tumors (ESTs), which may rarely exhibit areas of sex cord-like differentiation, or whether it is a distinct uterine neoplasm unrelated to ESTs. Recently, several studies have revealed a recurrent t(7;17) translocation resulting in a JAZF1-JJAZ1 gene fusion in over 60% of EST and its variants, including 2 out of 4 endometrial stromal tumors with sex cord-like elements (ESTSCLE). We examined UTROSCTs for evidence of the JAZF1-JJAZ1 gene fusion by fluorescence in situ hybridization and by reverse transcriptase polymerase chain reaction in 24 and 20 cases, respectively. The JAZF1-JJAZ1 gene fusion was not identified in any tumor by either method. Although we cannot entirely exclude that UTROSCT represents a variant of ESTSCLE which lacks this translocation, our findings suggest that UTROSCT does not share the genetic mechanism common to the majority of ESTs with or without sex cord-like differentiation, and therefore most likely represents a distinct neoplasm unrelated to ESTSCLE.