Promotion of Cancer Cell Proliferation by Cleaved and Secreted Luminal Domains of ER Stress Transducer BBF2H7
Year: 2015
Type: article
Abstract: BBF2H7 is an endoplasmic reticulum (ER)-resident transmembrane basic leucine zipper (bZIP) transcription factor that is cleaved at the transmembrane domain by regulated intramembrane proteolysis in response to ER stress. The cleaved cytoplasmic N-terminus containing transcription activation and bZIP domains translocates into the nucleus to promote the expression of target genes. In chondrocytes, the cleaved luminal C-terminus is extracellularly secreted and facilitates proliferation of neighboring cells through activation of Hedgehog signaling. In the present study, we found that Bbf2h7 expression levels significantly increased by 1.070-2.567-fold in several tumor types including glioblastoma compared with those in respective normal tissues, using the ONCOMINE Cancer Profiling Database. In some Hedgehog ligand-dependent cancer cell lines including glioblastoma U251MG cells, the BBF2H7 C-terminus was secreted from cells into the culture media and promoted cancer cell proliferation through activation of Hedgehog signaling. Knockdown of Bbf2h7 expression suppressed the proliferation of U251MG cells by downregulating Hedgehog signaling. The impaired cell proliferation and Hedgehog signaling were recovered by addition of BBF2H7 C-terminus to the culture medium of Bbf2h7-knockdown U251MG cells. These data suggest that the secreted luminal BBF2H7 C-terminus is involved in Hedgehog ligand-dependent cancer cell proliferation through activation of Hedgehog signaling. Thus, the BBF2H7 C-terminus may be a novel target for the development of anticancer drugs.
Source: PLoS ONE
Institutions: Hiroshima University, Hiroshima University Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Awards: Involvement of novel ubiquitin ligases in the pathogenic mechanism of Alzheimer's disease and drug discovery for fundamental therapeutic agent, 小胞体ストレスセンサーシグナルに着目した神経変性疾患に対する包括的治療基盤の構築, The molecular mechanisms of cell-to-cell communication by a cleaved endoplasmic reticulum stress transducer, The role of unfolded protein response in brown adipocytes, Molecular mechanisms of biological regulation by endoplasmic reticulum stress response, 小胞体ストレス応答による生理機能制御, Luman, an ER membrane-bound transcription factor, is involved in osteoclastogenesis, ユビキチンリガーゼ破綻による神経変性疾患発症機構, The analysis of the skeletal cell differentiation regulated by endoplasmic reticulum stress transducers.
OpenAlex ID: W840559482