Cep55 overexpression promotes genomic instability and tumorigenesis in mice

Abstract

High expression of centrosomal protein CEP55 has been correlated with clinico-pathological parameters across multiple human cancers. Despite significant in vitro studies and association of aberrantly overexpressed CEP55 with worse prognosis, its causal role in vivo tumorigenesis remains elusive. Here, using a ubiquitously overexpressing transgenic mouse model, we show that Cep55 overexpression causes spontaneous tumorigenesis and accelerates Trp53+/− induced tumours in vivo. At the cellular level, using mouse embryonic fibroblasts (MEFs), we demonstrate that Cep55 overexpression induces proliferation advantage by modulating multiple cellular signalling networks including the hyperactivation of the Pi3k/Akt pathway. Notably, Cep55 overexpressing MEFs have a compromised Chk1-dependent S-phase checkpoint, causing increased replication speed and DNA damage, resulting in a prolonged aberrant mitotic division. Importantly, this phenotype was rescued by pharmacological inhibition of Pi3k/Akt or expression of mutant Chk1 (S280A) protein, which is insensitive to regulation by active Akt, in Cep55 overexpressing MEFs. Moreover, we report that Cep55 overexpression causes stabilized microtubules. Collectively, our data demonstrates causative effects of deregulated Cep55 on genome stability and tumorigenesis which have potential implications for tumour initiation and therapy development.

Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis

“…CEP55 was initially described as an abscission component serving to regulate cellular segregation during cytokinesis [ 1 ]. Later, the finding of CEP55 regulatory roles in PI3K/AKT survival signaling illustrated the importance of this protein, especially in cancer where transcriptional upregulation of CEP55 widely contributes to cancer progression [ 2 , 29 ]. Interestingly, activating mutations in genes of the PI3K pathway has been shown to cause a wide range of brain and body overgrowth disorders [ 30 ] with phenotypic severity highly dependent on the extent of activation of the pathway [ 31 ].…”

An Improved, Assay Platform Agnostic, Absolute Single Sample Breast Cancer Subtype Classifier

“…Second, limiting the pool of total genes based on their functional association further reduced the search space and the risk for selecting a false gene. By using the PAM50 genes, we greatly reduced the number of cases by a factor of~10 20 , without a loss in accuracy. Lastly, pre-selection of four seed genes was done based on the same rationale (i.e., securing functional relevance and model generality while reducing search space).…”

“…The genes used in MiniABS are known to be involved in biologic characteristics, such as proliferation (MYBL2, MKI67, and CEP55), HER2 signaling (ERBB2), growth factor signaling (FGFR4), ER signaling (FOXA1, MLPH, ESR1, and PGR), and Basal phenotype (KRT17, and SFRP1) [19][20][21]. Additionally, SFRP1 is a known Basal-like marker, and MYBL2 is a LumA-specific cellular proliferation marker [8,22].…”

CEP55 Inhibitor: Extensive Computational Approach Defining a New Target of Cell Cycle Machinery Agent

“…Previous studies of aberrant phenotypes and prognostic significance in the altered expression of CEP55 are summarized in Table 1. CEP55 overexpression correlates with the cancer aggressiveness and poor prognosis of patients with breast cancer 6,22,23 . In cervical cancer, CEP55 protein levels are elevated in tumors as compared with adjacent normal tissue and correlated with lymph node metastasis and advanced tumor stage 24 .…”