1: Haem-dependent dimerization of PGRMC1/sigma-2 receptor facilitates cancer proliferation and chemoresistance.

Nature Communications
18 MARCH 2016

Yasuaki Kabe, Takanori Nakane, Ikko Koike, Tatsuya Yamamoto, Yuki Sugiura, Erisa Harada, Kenji Sugase, Tatsuro Shimamura, Mitsuyo Ohmura, Kazumi Muraoka, Ayumi Yamamoto, Takeshi Uchida, So Iwata, Yuki Yamaguchi, Elena Krayukhina, Masanori Noda, Hiroshi Handa, Koichiro Ishimori, Susumu Uchiyama, Takuya Kobayashi and Makoto Suematsu

A research group led by Lecturer Yasuaki Kabe and Professor Makoto Suematsu (at the time; currently President of AMED and Guest Professor) of the Department of Biochemistry has succeeded for the first time in the world in the X-ray crystal structure analysis of PGRMC1, a membrane-bound heme protein highly expressed in malignant tumors. They were also the first in the world to elucidate the mechanism by which this molecule allows cancer cells to activate proliferation and acquire resistance to anticancer drugs. It was found that PGRMC1 forms a coordinate bond with heme via a tyrosine residue in the protein. This heme has a structure that protrudes from the protein surface, and two PGRMC1 molecules form a unique dimer by binding through hydrophobic stacking of their respective hemes. Such multimerization via heme polymerization is the first example of its kind in eukaryotes. The endogenous gas molecule CO is increased by the stress-inducible enzyme heme oxygenase, and the team discovered that when CO binds to the heme on PGRMC1, the heme-heme polymerization dissociates, leading to the loss of PGRMC1 function. It was elucidated that dimerized PGRMC1 associates with the epidermal growth factor receptor (EGFR), which is involved in cancer proliferation, to enhance cancer growth signals. Furthermore, the PGRMC1 dimer also associates with the drug-metabolizing enzyme cytochrome P450, enhancing the degradation activity of anticancer drugs and thereby promoting chemotherapy resistance in cancer cells.

(Makoto Suematsu, President, Japan Agency for Medical Research and Development; 62nd Graduating Class, Department of Biochemistry)

Proc. Natl. Acad. Sci .

U.S.A., in press.

Koji Oishi, Michihiko Aramaki, and Kazunori Nakajima

The cerebral cortex, the command center for information processing in the nervous system, is where information is input, processed, and output. These roles are carried out by various types of nerve cells present in the cerebral cortex. However, the detailed mechanisms of how different types of nerve cells differentiate were not well understood. This study investigated the nerve cells responsible for receiving information from outside the cerebral cortex (layer 4 of the cerebral cortex) and the nerve cells responsible for information processing (layers 2-3). The analysis focused on the transcription factors Rorb and Brn2, which are specifically expressed in these mature nerve cells, respectively. The results revealed that layers 2-3 and layer 4 have similar characteristics (a common transcription factor expression pattern) at an immature stage. Furthermore, it was discovered that during the differentiation process, the program promoting the differentiation of one type (dependent on Rorb and Brn2, respectively) inhibits the differentiation program of the other, effectively selecting and promoting the differentiation of only one type. Currently, there are high expectations for cell therapy for various diseases, which involves transplanting specific cells necessary for treatment that are created from sources like iPS cells. The results of this research are expected to potentially contribute to the advancement of this field.

(Koji Oishi and Kazunori Nakajima, Department of Anatomy; 67th Graduating Class)

Am J Respir Crit Care Med .

2016 Jan 21.

Hashimoto K, Besla R, Zamel R, Juvet S, Kim H, Azad S, Waddell TK, Cypel M, Liu M, Keshavjee S.

Cell Stem Cell .

17(1):23-34, 2015

Yamashita M, Nitta E, Suda T.