Regulation of Skp2 Levels by the Pim-1 Protein Kinase

Cen, Bo; Mahajan, Sandeep; Zemskova, Marina; Beharry, Zanna; Lin, Ying Wei; Cramer, Scott D.; Lilly, Michael B.; Kraft, Andrew S.

doi:10.1074/jbc.m110.137240

Cited by 27 publications

(24 citation statements)

References 60 publications

(97 reference statements)

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“…A natural model of altered levels of the Pim-1 protein kinase is the variation in the levels that occur during the cell cycle (16). To determine whether eIF4B S406 phosphorylation parallels the expression of Pim-1 during the cell cycle, HeLa cells were synchronized with a double thymidine block protocol and then released into normal medium.…”

Section: Resultsmentioning

confidence: 99%

“…The Pim-1-expressing construct as well as its ⌬N81 and K67M kinase-dead mutants was described previously (16). The plasmids expressing eIF4B and its S406A, S422A, and S406/422A mutants were previously described (17).…”

mentioning

confidence: 99%

“…Standard biotin-avidin complex immunohistochemistry was performed. Anti-Pim-1 antibody (19F7) was produced in this laboratory (16). The anti-MET antibody used in these experiments was purchased from Santa Cruz (sc-161).…”

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confidence: 99%

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The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling

Cen

Xiong

Song

et al. 2014

Molecular and Cellular Biology

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MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration and invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression in multiple tumor cell types. The levels of the Pim-1 protein kinase show a positive correlation with the levels of MET protein in human tumor cell lines and patient-derived tumor materials. Using small interfering RNA (siRNA), Pim knockout mice, small-molecule inhibitors, and overexpression of Pim-1, we confirmed this correlation and found that Pim-1 kinase activity regulates HGF-induced tumor cell migration, invasion, and cell scattering. The novel biochemical mechanism for these effects involves the ability of Pim-1 to control the translation of MET by regulating the phosphorylation of eukaryotic initiation factor 4B (eIF4B) on S406. This targeted phosphorylation is required for the binding of eIF4B to the eIF3 translation initiation complex. Importantly, Pim-1 action was validated by the evaluation of patient blood and bone marrow from a phase I clinical trial of a Pim kinase inhibitor, AZD1208. These results suggest that Pim inhibitors may have an important role in the treatment of patients where MET is driving tumor biology.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling

Cen

Xiong

Song

et al. 2014

Molecular and Cellular Biology

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“…PIM and Akt regulate p27 kip expression levels at both the transcriptional and protein levels: 1) repression of p27 kip transcription via direct phosphorylation and inactivation of the FoxO1a and FoxO3a transcription factors, which drive p27 kip expression and 2) direct phosphorylation of p27 kip at Thr157, promoting its interaction with 14–3–3 proteins and proteasomal degradation in the cytoplasm (Fujita et al, 2002; Morishita et al, 2008). In addition, PIM kinases directly phosphorylate SKP2, the putative E3 ligase for p27, at Thr417, which stabilizes SKP2, enhancing the proteasomal degradation of p27 (Cen et al, 2010). Interestingly, SKP2 was reported to ubiquitinylate Akt and increase its activity in response to EGF, indicating that a positive feedback loop may exist between PIM and Akt in certain cellular contexts (Lin et al, 2009).…”

Section: Proviral Integration Site For Moloney Murine Leukemia Virmentioning

confidence: 99%

PIM kinase (and Akt) biology and signaling in tumors

Warfel

Kraft

2015

Pharmacology & Therapeutics

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The initiation and progression of human cancer is frequently linked to the uncontrolled activation of survival kinases. Two such pro-survival kinases that are commonly amplified in cancer are PIM and Akt. These oncogenic proteins are serine/threonine kinases that regulate tumorigenesis by phosphorylating substrates that control the cell cycle, cellular metabolism, proliferation, and survival. Growing evidence suggests that cross-talk exists between the PIM and Akt kinases, indicating that they control partially overlapping survival signaling pathways that are critical to the initiation, progression, and metastatic spread of many types of cancer. The PI3K/Akt signaling pathway is activated in many human tumors, and it is well established as a promising anticancer target. Likewise, based on the role of PIM kinases in normal and tumor tissues, it is clear that this family of kinases represents an interesting target for anticancer therapy. Pharmacological inhibition of PIM has the potential to significantly influence the efficacy of standard and targeted therapies. This review focuses on the regulation of PIM kinases, their role in tumorigenesis, and the biological impact of their interaction with the Akt signaling pathway on the efficacy of cancer therapy.

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“…The cell cycle is regulated by various factors, including cyclin, cyclin-dependent kinases (CDKs) and CDK interacting protein (cip)/kinase inhibitory protein (kip). S-phase kinase-associated protein 2 (Skp2) mainly induces the degradation of CDK inhibitors, including p21 cip1 , p27 kip1 and p57 kip2 (19)(20)(21). As an F-box protein, Skp2 is a key regulator for cell cycle progression.…”

Section: Introductionmentioning

confidence: 99%

Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma

Chen¹,

Mo²,

Yu³

et al. 2014

Molecular Medicine Reports

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Abstract. Colon cancer is a common type of malignancy in the digestive system. The aim of the present study was to investigate the role of S-phase kinase-associated protein 2 (Skp2) in colon carcinoma and to identify whether depletion of Skp2 by Skp2-RNA interference (RNAi) attenuates the proliferation and migration of colon carcinoma. Three pairs of small interfering (si)RNA were designed based on the Skp2 gene sequence and the most effective one was used to silence the Skp2 gene in SW620 cells. Subsequent to the interference, quantitative polymerase chain reaction and western blot analysis were used for detecting the expression of Skp-2 mRNA and protein, respectively. The data demonstrated that the Skp2-siRNA effectively inhibited proliferation (P<0.01), increased the levels of apoptosis and induced G 0 /G 1 phase arrest of the SW620 cells (P<0.01). Transfection of the Skp2 siRNA into SW620 cells effectively reduced Skp2 protein levels, while p27 protein levels increased. In the in vivo experiments, a lentiviral vector of the Skp2-RNAi transfected into SW620 cells markedly inhibited Skp2 expression, as detected by immunohistochemical analysis of nude mice. Additionally, tumorigenicity experiments showed that inhibition of Skp2 significantly increased the survival rate of nude mice. Thus, the in vitro and in vivo results demonstrated that interference of Skp2 expression significantly inhibited the proliferation and induced the apoptosis of SW620 cells. This suggests that Skp2 protein has an important role in the progression of colon cancer. Therefore, Skp2 may enable the early diagnosis of colon cancer and provide new insights into molecular targets for cancer therapy.

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Regulation of Skp2 Levels by the Pim-1 Protein Kinase

Cited by 27 publications

References 60 publications

The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling

The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling

PIM kinase (and Akt) biology and signaling in tumors

Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma

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