Oncogenic function of p34SEI-1 via NEDD4-1-mediated PTEN ubiquitination/degradation and activation of the PI3K/AKT pathway

Abstract

Abstract.A 34-KD protein encoded by the SEI-1 gene (p34 ), is a relatively recently discovered oncoprotein that has multiple important biological functions. Our data show that p34 SEI-1 enhances cancer cell survival and promotes tumorigenesis by downregulating the tumor suppressor PTEN, a negative regulator of the PI3K/AKT signaling pathway, and therefore activating the PI3K/AKT signaling pathway. In this process, p34 SEI-1 positively affects NEDD4-1 gene expression both at the transcriptional and protein levels. Furthermore, the expression levels of p34 SEI-1 and NEDD4-1 were found to be coordinated in tumor tissues obtained from patients with breast cancer. We also show that p34 SEI-1 affects the subcellular localization of PTEN.

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

“…An independent study by Jung et al confirmed NEDD4-1 stabilization and PTEN degradation induced by p34SEI-1 overexpression [37]. Interestingly, p34SEI-1 overexpression also resulted in increased PTEN nuclear localization, suggesting again the possibly highly contextual nature of functional consequences of NEDD4-1's regulation of PTEN.…”

“…NEDD4-1 is frequently overexpressed in many types of human cancers including gastric carcinomas [35], colorectal [36], breast [37] and non-small cell lung carcinomas [38]. Suppression of NEDD4-1 expression in cells derived from these cancers can significantly reduce tumor cell growth both in vitro and in animal models.…”

“…NEDD4-1 is under transcriptional regulation by two transcription factors FoxM1 [50] and p34SEI-1 [37], both of which have been shown to promote oncogenesis by upregulating NEDD4-1. Interestingly, Hong and colleagues recently demonstrated that p34SEI-1, but not its close homologs SEI-2 or SEI-3, can potentiate the tumorigenic activities of NEDD4-1 through direct binding to NEDD4-1 [36].…”

Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells

“…High PTEN expression may be due to the cancer cell proliferation and DNA double chain fractures (26,27). PTEN is one of the key regulation factors in the process of DNA repair and the expression is then increased in order for it to participate in the process of cancer development (26,27). In previous studies, PTEN was tested in PCa and hyperplastic prostate tissues, and it was observed to be mainly expressed in PCa tissues and in the cell nuclei of hyperplastic prostate tissues (28,29).…”

“…High PTEN expression may be due to the cancer cell proliferation and DNA double chain fractures (26,27). PTEN is one of the key regulation factors in the process of DNA repair and the expression is then increased in order for it to participate in the process of cancer development (26,27).…”