Toshikazu Nagao

Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas.

Hepatocellular carcinoma (HCC) is one of the most common cancers in Asia and Africa, where hepatitis virus infection and exposure to specific liver carcinogens are prevalent. Although inactivation of some tumor suppressor genes such as p53 and p16INK4Ahas been identified, no known oncogene is commonly activated in hepatocellular carcinomas. Here we have isolated genes overexpressed in hepatocellular carcinomas by cDNA subtractive hybridization, and identified an oncoprotein consisting of six ankyrin repeats (gankyrin). The expression of gankyrin was increased in all 34 hepatocellular carcinomas studied. Gankyrin induced anchorage-independent growth and tumorigenicity in NIH/3T3 cells. Gankyrin bound to the product of the retinoblastoma gene (RB1), increasing its phosphorylation and releasing the activity of the transcription factor E2F-1. Gankyrin accelerated the degradation of RB1 in vitro and in vivo, and was identical to or interacted with a subunit of the 26S proteasome. These results demonstrate the importance of ubiquitin–proteasome pathway in the regulation of cell growth and oncogenic transformation, and indicate that gankyrin overexpression contributes to hepatocarcinogenesis by destabilizing RB1.

A novel protein overexpressed in hepatoma accelerates export of NF-κB from the nucleus and inhibits p53-dependent apoptosis

NF-kappa B is a transcription factor that can protect from or contribute to apoptosis. Here we report identification of HSCO that binds to NF-kappa B and inhibits apoptosis. HSCO mRNA was overexpressed in 20 of 30 hepatocellular carcinomas analyzed. Overexpression of HSCO inhibited caspase 9 activation and apoptosis induced by DNA damaging agents, while it augmented apoptosis induced by TNFalpha. Like I kappa B alpha, HSCO inhibited NF-kappa B activity and abrogated p53-induced apoptosis. However, the underlying mechanism was different. HSCO is a nuclear-cytoplasmic shuttling protein, bound to RelA NF-kappa B, and HSCO sequestered it in the cytoplasm by accelerating its export from the nucleus. These results suggest that overexpression of HSCO suppresses p53-induced apoptosis by preventing nuclear localization of NF-kappa B during signaling and thus contributes to hepatocarcinogenesis.

Expression of protein tyrosine phosphatase PTP-RL10 and its isoform in the mouse testis.

Background : The cytoplasmic‐type protein tyrosine phosphatase PTP‐RL10/PTPD1/PTP2E contains an ezrin‐like domain and associates with the c‐Src protein tyrosine kinase. Because tyrosine phosphorylation regulated by protein tyrosine kinases and phosphatases is involved in activation, migration, differentiation and proliferation of various cell types, the expression of PTP‐RL10 and c‐src in the mouse testis was investigated.

Opening of shortcut circuits between visual and retrosplenial granular cortices of rats.

Traveling neural signals may try to find suitable paths of propagation in cortical circuits. We examined the behavior of electrically evoked signals from primary visual cortex (Oc1) to granular retrosplenial cortex (RSG) in rat brain slices under caffeine application. With continued electrical stimulation, evoked signals propagated from Oc1 to RSG along the upper layer of the secondary visual cortex (Oc2) and agranular retrosplenial cortex (RSA), but on further continuation of stimulation, a new shortcut pathway along the deep layer between Oc2 and RSG was opened. Circuitry changes reduced the signal traveling time by about 40 ms. Cortical neural circuits between Oc1 and RSG may thus have the ability to open a shortcut circuit in a use-dependent manner.