An Akt3 Splice Variant Lacking the Serine 472 Phosphorylation Site Promotes Apoptosis and Suppresses Mammary Tumorigenesis

Suyama, Kimita; Yao, Jian; Liang, Hongying; Benard, Outhiriaradjou; Loudig, Olivier; Amgalan, Dulguun; McKimpson, Wendy M.; Phillips, Greg R.; Segall, Jeffrey E.; Wang, Yihong; Fineberg, Susan; Norton, Larry; Kitsis, Richard N.; Hazan, Ronen

doi:10.1158/0008-5472.can-15-1462

Cited by 14 publications

(16 citation statements)

References 45 publications

(73 reference statements)

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“…AKT has been reported to rapidly accumulate in mitochondria following PI3K activation (30). In addition, previous studies have revealed that p-AKT is a crucial modulator of cellular processes, including cell survival (31,32), apoptosis (33,34), the cell cycle (35,36) and glycolysis (37,38) in various types of cancer. The findings of the present study suggested that the pathways downstream of AKT, including the p53 signaling pathway, NF-κB signaling pathway, apoptosis, FOXO signaling pathway, the cell cycle, glycolysis/gluconeogenesis, MAPK signaling pathway and the mTOR signaling pathway, were regulated by MRPL33-L and MRPL33-S; however, further investigation into the biological effects of MRPL33-L and MRPL33-S in gastric cancer is required.…”

Section: Discussionmentioning

confidence: 99%

Isoforms S and L of MRPL33 from alternative splicing have isoform‑specific roles in the chemoresponse to epirubicin in gastric cancer cells via the PI3K/AKT signaling pathway

Feng

Gao³

et al. 2019

Int J Oncol

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Drug resistance is a major cause of cancer-associated mortality. Epirubicin-based chemotherapy initially benefits patients with metastatic or advanced gastric cancer; however, tumor recurrence can occur following several courses of treatment. Mitochondrial ribosomal protein L33 (MRPL33)-long (L) and MRPL33-short (S), isoforms of MRPL33 that arise from AS, have been reported to regulate cell growth and apoptosis in cancer; however, few studies have evaluated the roles of MRPL33-L and MRPL33-S in gastric cancer. In the present study, MRPL33-L was demonstrated to be significantly more abundant in gastric tumor tissues than the MRPL33-S isoform. MRPL33-S promoted chemosensitivity to epirubicin in gastric cancer as demonstrated by a chemoresponse assay; chemosensitivity was suppressed in response to MRPL33-L. Gene microarray analysis was performed to investigate the underlying mechanisms. Bioinformatic analysis revealed that overexpression of MRPL33-L and MRPL33-S served critical roles in transcription, signal transduction and apoptosis. In particular, the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway was markedly regulated. A total of 36 target genes, including PIK3 regulatory subunit α, AKT2, cAMP response element-binding protein (CREB) 1, forkhead box 3, glycogen synthase kinase 3β and mammalian target of rapamycin, which are involved in the PI3K/AKT signaling pathway, were selected for further investigation via protein-protein interaction network and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Furthermore, western blot analysis indicated that MRPL33-S promoted the chemoresponse to epirubicin by deactivating PI3K/AKT/CREB signaling and inducing apoptosis, while MRPL33-L had the opposite effects. In conclusion, the results of the present study revealed that isoforms S and L of MRPL33, which arise from alternative splicing, exhibited opposing roles in the chemoresponse to epirubicin in gastric cancer via the PI3K/AKT signaling pathway. These findings may contribute to the development of potential therapeutic strategies for the resensitization of patients with gastric cancer to epirubicin treatment.

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Section: Discussionmentioning

confidence: 99%

Isoforms S and L of MRPL33 from alternative splicing have isoform‑specific roles in the chemoresponse to epirubicin in gastric cancer cells via the PI3K/AKT signaling pathway

Feng

Gao³

et al. 2019

Int J Oncol

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“…Akt3 generates two alternatively spliced variants, Akt3/-S472 and Akt3/+S472, the former lacks the key regulatory serine 472 phosphorylation site compared to the full-length (Akt3/+S472). While over-expression of Akt3/-S472 has been shown to suppress mammary tumorigenesis, Akt3/+S472 had no effect on malignant cell growth [28]. Thus, spliced variants have been demonstrated to perform different functions compared to the full-length protein.…”

Section: Discussionmentioning

confidence: 99%

A Novel Splice Variant of the Masculinizing Gene Masc with piRNA-Cleavage-Site Defect Functions in Female External Genital Development in the Silkworm, Bombyx mori

Qin

Wen

et al. 2019

Biomolecules

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In the silkworm, the sex-determination primary signal Fem controls sex differentiation by specific binding of Fem-derived piRNA to the cleavage site in Masc mRNA, thus inhibiting Masc protein production in the female. In this study, we identified a novel splicing isoform of Masc, named Masc-S, which lacks the intact sequence of the cleavage site, encoding a C-terminal truncated protein. Results of RT-PCR showed that Masc-S was expressed in both sexes. Over-expression of Masc-S and Masc in female-specific cell lines showed that Masc-S could be translated against the Fem-piRNA cut. By RNA-protein pull-down, LC/MS/MS, and EMSA, we identified a protein BmEXU that specifically binds to an exclusive RNA sequence in Masc compared to Masc-S. Knockdown of Masc-S resulted in abnormal morphology in female external genital and increased expression of the Hox gene Abd-B, which similarly occurred by Bmexu RNAi. These results suggest that the splice variant Masc-S against Fem-piRNA plays an important role in female external genital development, of which function is opposite to that of full-length Masc. Our study provides new insights into the regulatory mechanism of sex determination in the silkworm.

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“…After the detection of AKT1 and AKT2 by Jones et al [21, 93], AKT3 was discovered a few years later [94, 95]. AKT3 is constituted of the two distinct splicing variants AKT3 + S472 and AKT3-S472, the latter one lacking the phosphorylation site on position S472 [96]. Different genes are encoding for the three isoforms: AKT1 is located at 14q32 [97], AKT2 at 19q13.1–13.2 [98] and AKT3 at 1q44 [99].…”

Section: The Three Akt Isoformsmentioning

confidence: 99%

“…Suyama et al investigated the role of AKT3 in a more differentiated manner, considering the two different splice variants AKT3 + S472 and AKT3-S472; the latter without the S472 phosphorylation site. Knockdown of AKT3-S472 in TNBC displays an enhanced tumor growth in vivo by downregulating Bim via activation of the MAPK/ERK pathway and therefore inhibition of BAX [96].…”

Section: Akt Isoform Specificity In Breast Cancer: Proliferation and mentioning

confidence: 99%

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Distinct functions of AKT isoforms in breast cancer: a comprehensive review

2019

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Background: AKT, also known as protein kinase B, is a key element of the PI3K/AKT signaling pathway. Moreover, AKT regulates the hallmarks of cancer, e.g. tumor growth, survival and invasiveness of tumor cells. After AKT was discovered in the early 1990s, further studies revealed that there are three different AKT isoforms, namely AKT1, AKT2 and AKT3. Despite their high similarity of 80%, the distinct AKT isoforms exert non-redundant, partly even opposing effects under physiological and pathological conditions. Breast cancer as the most common cancer entity in women, frequently shows alterations of the PI3K/AKT signaling. Main content: A plethora of studies addressed the impact of AKT isoforms on tumor growth, metastasis and angiogenesis of breast cancer as well as on therapy response and overall survival in patients. Therefore, this review aimed to give a comprehensive overview about the isoform-specific effects of AKT in breast cancer and to summarize known downstream and upstream mechanisms. Taking account of conflicting findings among the studies, the majority of the studies reported a tumor initiating role of AKT1, whereas AKT2 is mainly responsible for tumor progression and metastasis. In detail, AKT1 increases cell proliferation through cell cycle proteins like p21, p27 and cyclin D1 and impairs apoptosis e.g. via p53. On the downside AKT1 decreases migration of breast cancer cells, for instance by regulating TSC2, palladin and EMT-proteins. However, AKT2 promotes migration and invasion most notably through regulation of β-integrins, EMT-proteins and F-actin. Whilst AKT3 is associated with a negative ER-status, findings about the role of AKT3 in regulation of the key properties of breast cancer are sparse. Accordingly, AKT1 is mutated and AKT2 is amplified in some cases of breast cancer and AKT isoforms are associated with overall survival and therapy response in an isoform-specific manner. Conclusions: Although there are several discussed hypotheses how isoform specificity is achieved, the mechanisms behind the isoform-specific effects remain mostly unrevealed. As a consequence, further effort is necessary to achieve deeper insights into an isoform-specific AKT signaling in breast cancer and the mechanism behind it.

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An Akt3 Splice Variant Lacking the Serine 472 Phosphorylation Site Promotes Apoptosis and Suppresses Mammary Tumorigenesis

Cited by 14 publications

References 45 publications

Isoforms S and L of MRPL33 from alternative splicing have isoform‑specific roles in the chemoresponse to epirubicin in gastric cancer cells via the PI3K/AKT signaling pathway

Isoforms S and L of MRPL33 from alternative splicing have isoform‑specific roles in the chemoresponse to epirubicin in gastric cancer cells via the PI3K/AKT signaling pathway

A Novel Splice Variant of the Masculinizing Gene Masc with piRNA-Cleavage-Site Defect Functions in Female External Genital Development in the Silkworm, Bombyx mori

Distinct functions of AKT isoforms in breast cancer: a comprehensive review

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