PAX2 mutations cause renal-coloboma syndrome (RCS), a rare multi-system developmental abnormality involving optic nerve colobomas and renal abnormalities. End-stage renal failure is common in RCS, but the mechanism by which PAX2 mutations lead to renal failure is unknown. PAX2 is a member of a family of developmental genes containing a highly conserved 'paired box' DNA-binding domain, and encodes a transcription factor expressed primarily during fetal development in the central nervous system, eye, ear and urogenital tract. Presently, the role of PAX2 during kidney development is poorly understood. To gain insight into the cause of renal abnormalities in patients with PAX2 mutations, kidney anomalies were analyzed in patients with RCS, including a large Brazilian kindred in whom a new PAX2 mutation was identified. In a total of 29 patients, renal hypoplasia was the most common congenital renal abnormality. To determine the direct effects of PAX2 mutations on kidney development fetal kidneys of mice carrying a Pax2 (1Neu)mutation were examined. At E15, heterozygous mutant kidneys were approximately 60% of the size of wild-type littermates, and the number of nephrons was strikingly reduced. Heterozygous 1Neu mice showed increased apoptotic cell death during fetal kidney development, but the increased apoptosis was not associated with random stochastic inactivation of Pax2 expression in mutant kidneys; Pax2 was shown to be biallelically expressed during kidney development. These findings support the notion that heterozygous mutations of PAX2 are associated with increased apoptosis and reduced branching of the ureteric bud, due to reduced PAX2 dosage during a critical window in kidney development.

Cervical cancer is the third most common cancer and the third leading cause of death among women. However, the standard treatment for cervical cancer includes cisplatin, which can cause side effects such as hematological damage or renal toxicity. New innovations in cervical cancer treatment focus on developing more effective and better-tolerated therapies such as Sp1-targeting drugs. Previous studies suggested that mithramycin A (Mith) inhibits the growth of various cancers by decreasing Sp1 protein. However, how Sp1 protein is decreased by Mith is not clear. Few studies have investigated the regulation of Sp1 protein by proteasome-dependent degradation as a possible control mechanism for the regulation of Sp1 in cancer cells. Here, we show that Mith decreased Sp1 protein by inducing proteasome-dependent degradation, thereby suppressing cervical cancer growth through a DR5/caspase-8/Bid signaling pathway. We found that prolonged Mith treatment was well tolerated after systemic administration to mice carrying cervical cancer cells. Reduction of body weight was minimal, indicating that Mith was a good therapeutic candidate for treatment of cancers in which Sp1 is involved in promoting and developing disease.

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Cruciferous vegetables have been shown to have the possibility to protect against multistep carcinogenesis. β-Phenylethyl isothiocyanate (PEITC) is one component of these vegetables demonstrated to help fight many types of cancer. The present study examined the apoptotic effects of PEITC and its molecular mechanism in human cervical cancer cell lines (HEp-2 and KB). PEITC induced apoptosis to inhibit cell proliferation. According to the protein chip assay, PEITC increased the expression of the death receptors (DR4 and DR5) and cleaved caspase-3 compared to the DMSO treatment group. PEITC also induced caspase-8 and truncated BID. PEITC down-regulated the phosphorylation of extracellular-related kinase (ERK)1/2, whereas neither phospho-c-Jun NH(2)-terminal kinases (JNK) nor phospho-p38 MAPK was changed. The role of ERK in PEITC-induced apoptosis was also investigated using MEK inhibitor (PD98059). PD98059 increased the expression of DR4 and DR5, activated caspase-3, and cleaved PARP. In addition, PEITC decreased the phosphorylation of MEK. Therefore, the apoptotic mechanism of PEITC in cervical cancer cells involves the induction of DR4 and DR5 through the inactivation of ERK and MEK.

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