Brain Expressed and X-Linked (Bex) Proteins Are Intrinsically Disordered Proteins (IDPs) and Form New Signaling Hubs

Girard²,

Transl. Lung Cancer Res.

et al. 2018

198

250

Background: Small cell lung cancer (SCLC) is a deadly, high grade neuroendocrine (NE) tumor without recognized morphologic heterogeneity. However, over 30 years ago we described a SCLC subtype with "variant" morphology which did not express some NE markers and exhibited more aggressive growth. Methods:To quantitate NE properties of SCLCs, we developed a 50-gene expression-based NE score that could be applied to human SCLC tumors and cell lines, and genetically engineered mouse (GEM) models. We identified high and low NE subtypes of SCLC in all of our sample types, and characterized their properties. Results:We found that 16% of human SCLC tumors and 10% of SCLC cell lines were of the low NE

Section: Discussionmentioning

confidence: 99%

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

Girard²,

Transl. Lung Cancer Res.

et al. 2018

198

250

“…However, BEX2 is highly expressed in a subset of estrogen receptor-positive breast cancers 10 and glioblastoma 11 and plays a key role in promoting cell survival and growth in breast cancer cells. The BEX protein family has been reported to contain long regions of intrinsic disorder that may form signaling hubs, and the hubs formed by intrinsically disordered proteins play important roles in cellular differentiation and cancer 6. Thus, BEX2 appears to play different roles in different tumor types.…”

Section: Discussionmentioning

confidence: 99%

“…Brain-expressed X-linked (BEX) genes are a family of genes that reside on the mammalian X chromosome, and BEX proteins are involved in the cell cycle, cancer and tumor growth 6,7. BEX2 is highly expressed in the embryonic brain and can interact with transcriptional factor LMO2 to regulate transcriptional activity 8.…”

Section: Introductionmentioning

confidence: 99%

BEX2 promotes tumor proliferation in colorectal cancer

Xiao

Chen

et al. 2017

Int. J. Biol. Sci.

BEX2 has been suggested to promote the tumor growth in breast cancer and glioblastoma, while inhibit the proliferation of glioma cells. Thus, the role of BEX2 in tumor was still in debate. Additionally, the biological functions of BEX2 in colorectal cancer (CRC) have not yet been clarified. Here, we reported that BEX2 was overexpressed in advanced CRC from both the GSE14333 database and fresh CRC tissue specimens, and positively correlated with clinical staging. Knockdown of BEX2 significantly decreased the in vitro proliferation of SW620 colorectal cancer cells, suppressed subcutaneous xenograft growth and enhanced the survival of mice with cecal tumors. These effects were mainly mediated by the JNK/c-Jun pathway. Knockdown of BEX2 inhibited JNK/c-Jun phosphorylation, while BEX2 overexpression activated JNK/c-Jun phosphorylation. Moreover, the administration of the JNK-specific inhibitor SP600125 to SW620 with BEX2 overexpression abolished the effect of BEX2 on SW620 cell proliferation. This study reveals that BEX2 promotes colorectal cancer cell proliferation via the JNK/c-Jun pathway, suggesting BEX2 as a potential candidate target for the treatment of CRC.

“…We speculated that OMP modulated Ca 2+ -mediated PKC/ MAPK signaling, which is the main pathway responsible for TRH-induced PRL expression. Previous studies have shown that OMP modulates Ca 2+ extrusion from olfactory sensory neurons by directly interacting with brainexpressed X-linked 1 (Bex1) proteins, which can also bind to the Ca 2+ -dependent modulator, calmodulin (CaM) 8,11,13,39,40 . The OMP-Bex1-CaM interaction can explain the desensitization to TRH stimulation that is observed in the absence of OMP.…”

Section: Discussionmentioning

confidence: 99%

Olfactory marker protein regulates prolactin secretion and production by modulating Ca2+ and TRH signaling in lactotrophs

Ku¹,

Kang²,

Kim³

et al. 2018

EJEA

Olfactory marker protein (OMP) is a marker of olfactory receptor-mediated chemoreception, even outside the olfactory system. Here, we report that OMP expression in the pituitary gland plays a role in basal and thyrotropin-releasing hormone (TRH)-induced prolactin (PRL) production and secretion. We found that OMP was expressed in human and rodent pituitary glands, especially in PRL-secreting lactotrophs. OMP knockdown in GH4 rat pituitary cells increased PRL production and secretion via extracellular signal-regulated kinase (ERK)1/2 signaling. Real-time PCR analysis and the Ca 2+ influx assay revealed that OMP was critical for TRH-induced PRL secretion. OMP-knockout mice showed lower fertility than control mice, which was associated with increased basal PRL production via activation of ERK1/2 signaling and reduced TRH-induced PRL secretion. However, both in vitro and in vivo results indicated that OMP was only required for hormone production and secretion because ERK1/2 activation failed to stimulate cell proliferation. Additionally, patients with prolactinoma lacked OMP expression in tumor tissues with hyperactivated ERK1/2 signaling. These findings indicate that OMP plays a role in PRL production and secretion in lactotrophs through the modulation of Ca 2+ and TRH signaling.