Cep55 overexpression causes male‐specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling

Abstract

Spermatogenesis is a dynamic process involving self-renewal and differentiation of spermatogonial stem cells, meiosis, and ultimately, the differentiation of haploid spermatids into sperm. Centrosomal protein 55 kDa (CEP55) is necessary for somatic cell abscission during cytokinesis. It facilitates equal segregation of cytoplasmic contents between daughter cells by recruiting endosomal sorting complex required for transport machinery (ESCRT) at the midbody. In germ cells, CEP55, in partnership with testes expressed-14 (TEX14) protein, has also been shown to be an integral component of intercellular bridge before meiosis. Various in vitro studies have demonstrated a role for CEP55 in multiple cancers and other diseases. However, its oncogenic potential in vivo remains elusive. To investigate, we generated ubiquitously overexpressing Cep55 transgenic ( Cep55) mice aiming to characterize its oncogenic role in cancer. Unexpectedly, we found that Cep55 male mice were sterile and had severe and progressive defects in spermatogenesis related to spermatogenic arrest and lack of spermatids in the testes. In this study, we characterized this male-specific phenotype and showed that excessively high levels of Cep55 results in hyperactivation of PI3K/protein kinase B (Akt) signaling in testis. In line with this finding, we observed increased phosphorylation of forkhead box protein O1 (FoxO1), and suppression of its nuclear retention, along with the relative enrichment of promyelocytic leukemia zinc finger (PLZF) -positive cells. Independently, we observed that Cep55 amplification favored upregulation of ret ( Ret) proto-oncogene and glial-derived neurotrophic factor family receptor α-1 ( Gfra1). Consistent with these data, we observed selective down-regulation of genes associated with germ cell differentiation in Cep55-overexpressing testes at postnatal day 10, including early growth response-4 ( Egr4) and spermatogenesis and oogenesis specific basic helix-loop-helix-1 ( Sohlh1). Thus, Cep55 amplification leads to a shift toward the initial maintenance of undifferentiated spermatogonia and ultimately results in progressive germ cell loss. Collectively, our findings demonstrate that Cep55 overexpression causes change in germ cell proportions and manifests as a Sertoli cell only tubule phenotype, similar to that seen in many azoospermic men.-Sinha, D., Kalimutho, M., Bowles, J., Chan, A.-L., Merriner, D. J., Bain, A. L., Simmons, J. L., Freire, R., Lopez, J. A., Hobbs, R. M., O'Bryan, M. K., Khanna, K. K. Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling.

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

“…Immunohistochemistry (IHC) analysis was performed on primary 4T1.2 tumors as described previously. 25 Immunostaining was performed with the following primary antibodies: anti-CD4 1:50 (Mouse, 14-9766, eBioSciences, San Diego, CA) and anti-CD8 1:75 (mouse, 14-0808, eBioSciences). ApopTag staining was performed using the ApopTag peroxidase in situ apoptosis detection kit (S7100; Millipore Sigma, Billerica, MA).…”

Cep55 overexpression promotes genomic instability and tumorigenesis in mice

“…To characterize the pathophysiological role of CEP55 overexpression in vivo , we utilised our recently reported transgenic mouse model 17 . Since Cep55 is highly overexpressed in multiple human cancers irrespective of its role in cell division (Supp.…”

“…We previously reported a Cep55 -overexpression mouse model that exhibits male-specific sterility by suppressing Foxo1 nuclear retention through hyperactivation of Pi3k/Akt signalling 17 . In this study, using the same mouse model, we demonstrate for the first time that Cep55 overexpression causes spontaneous tumorigenesis.…”

“…Likewise, CEP55 interacts with JAK2 kinase and promotes its phosphorylation 16 . We have recently shown that Cep55 overexpression causes male-specific sterility by suppressing Foxo1 nuclear retention through the PI3K/AKT pathway in mice 17 . Furthermore, we showed that CEP55 is a determinant of aneuploid cell fate during perturbed mitosis in breast cancers and could be targeted through MEK1/2-PLK1 inhibition 18 .…”

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

“…Gene expression analysis using reverse-transcriptase quantitative PCR (RT-qPCR) was performed using the LightCycler 480 (Roche, Basel, Switzerland) as described previously (55).…”