Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate.

Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis.

Runt-related transcription factor 2 attenuates the transcriptional activity as well as DNA damage-mediated induction of pro-apoptotic TAp73 to regulate chemosensitivity.

Although runt-related transcription factor 2 (RUNX2) is known to be an essential key transcription factor for osteoblast differentiation and bone formation, RUNX2 also plays a pivotal role in the regulation of p53-dependent DNA damage response. In the present study, we report that, in addition to p53, RUNX2 downregulates pro-apoptotic TAp73 during DNA damage-dependent cell death. Upon adriamycin (ADR) exposure, human osteosarcoma-derived U2OS cells underwent cell death in association with an upregulation of TAp73 and various p53/TAp73-target gene products together with RUNX2.

Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet.

Background: The transcription factor nuclear factor-E2-related factor-2 (Nrf2) inhibits lipid accumulation and oxidative stress in the liver by interfering with lipogenic pathways and inducing antioxidative stress genes.

Methods: The involvement of Nrf2 in defense against the development of steatohepatitis was studied in an experimental model induced by an atherogenic plus high-fat (Ath + HF) diet. Wild-type (WT) and Nrf2-null mice were fed the diet.

Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis.

Background: The transcription factor nuclear factor-E2-related factor-2 (Nrf2) is a key regulator for induction of hepatic antioxidative stress systems. We aimed to investigate whether activation of Nrf2 protects against steatohepatitis.

Method: Wild-type mice (WT), Nrf2 gene-null mice (Nrf2-null) and Keap1 gene-knockdown mice (Keap1-kd), which represent the sustained activation of Nrf2, were fed a methionine- and choline-deficient diet (MCDD) for 13 weeks and analyzed.

Deletion of nuclear factor-E2-related factor-2 leads to rapid onset and progression of nutritional steatohepatitis in mice.

Oxidative stress is a critical mediator in liver injury of steatohepatitis. The transcription factor Nrf2 serves as a cellular stress sensor and is a key regulator for induction of hepatic detoxification and antioxidative stress systems. The involvement of Nrf2 in defense against the development of steatohepatitis remains unknown.

Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems.

The transcription factor Nrf2 is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes and Mrp efflux transporters. We aimed to investigate whether Nrf2 activation counteracts liver injury associated with cholestasis. The role of Nrf2 activation in counteracting cholestatic liver injury was studied using a bile duct-ligation (BDL) model of Keap1 gene-knockdown (Keap1-kd) mice that represent the sustained activation of Nrf2 in the liver.