Protein Kinase C δ Stimulates Apoptosis by Initiating G1Phase Cell Cycle Progression and S Phase Arrest

ABSTRACT The transcription factor p73, a member of the p53 family of proteins, is involved in the regulation of cell cycle progression and apoptosis. However, the regulatory mechanisms controlling the distinct roles for p73 in these two processes have remained unclear. Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. We also characterized a second transactivation domain in the carboxy terminus of p73 within amino acid residues 381 to 399. This carboxy terminus transactivation domain was found to preferentially regulate genes involved in cell cycle progression. Moreover, its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388. Our results suggest that this novel posttranslational modification within the p73 carboxy terminus transactivation domain is involved in the context-specific guidance of p73 toward the selective induction of cell cycle arrest.

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A Cds1-Mediated Checkpoint Protects the MBF Activator Rep2 from Ubiquitination by Anaphase-Promoting Complex/Cyclosome-Ste9 at S-Phase Arrest in Fission Yeast

Molecular and Cellular Biology ◽

10.1128/mcb.00562-09 ◽

2009 ◽

Vol 29 (18) ◽

pp. 4959-4970 ◽

Cited By ~ 8

Author(s):

Zhaoqing Chu ◽

Majid Eshaghi ◽

Suk Yean Poon ◽

Jianhua Liu

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Transcriptional Activity ◽

S Phase ◽

Anaphase Promoting Complex ◽

Cell Recovery ◽

Cycle Progression ◽

Phase Arrest ◽

S Phase Arrest

ABSTRACT Transcription of the MluI cell cycle box (MCB) motif-containing genes at G1 phase is regulated by the MCB-binding factors (MBF) (also called DSC1) in Schizosaccharomyces pombe. Upon S-phase arrest, the MBF transcriptional activity is induced through the accumulation of the MBF activator Rep2. In this study, we show that the turnover of Rep2 is attributable to ubiquitin-mediated proteolysis. Levels of Rep2 oscillate during the cell cycle, with a peak at G1 phase, coincident with the MBF activity. Furthermore, we show that Rep2 ubiquitination requires the function of the E3 ligase anaphase-promoting complex/cyclosome (APC/C). Ste9 can be phosphorylated by the checkpoint kinase Cds1 in vitro, and its inhibition/phosphorylation at S-phase arrest is dependent on the function of Cds1. Our data indicate that the Cds1-dependent stabilization of Rep2 is achieved through the inhibition/phosphorylation of APC/C-Ste9 at the onset of S-phase arrest. Stabilization of Rep2 is important for stimulating transcription of the MBF-dependent genes to ensure a sufficient supply of proteins essential for cell recovery from S-phase arrest. We propose that oscillation of Rep2 plays a role in regulation of periodic transcription of the MBF-dependent genes during cell cycle progression.

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Involvement of p21Waf1/Cip1 in Protein Kinase C Alpha-Induced Cell Cycle Progression

Molecular and Cellular Biology ◽

10.1128/mcb.20.13.4580-4590.2000 ◽

2000 ◽

Vol 20 (13) ◽

pp. 4580-4590 ◽

Cited By ~ 86

Author(s):

Arnaud Besson ◽

V. Wee Yong

Keyword(s):

Cell Cycle ◽

Protein Kinase C ◽

Protein Kinase ◽

Cell Cycle Progression ◽

Glioma Cells ◽

Cycle Progression ◽

Kinase C ◽

Glioma Growth ◽

Necessary And Sufficient ◽

Α Activity

ABSTRACT Protein kinase C (PKC) plays an important role in the regulation of glioma growth; however, the identity of the specific isoform and mechanism by which PKC fulfills this function remain unknown. In this study, we demonstrate that PKC activation in glioma cells increased their progression through the cell cycle. Of the six PKC isoforms that were present in glioma cells, PKC α was both necessary and sufficient to promote cell cycle progression when stimulated with phorbol 12-myristate 13-acetate. Also, decreased PKC α expression resulted in a marked decrease in cell proliferation. The only cell cycle-regulatory molecule whose expression was rapidly altered and increased by PKC α activity was the cyclin-cyclin-dependent kinase (CDK) inhibitor p21Waf1/Cip1. Coimmunoprecipitation studies revealed that p21Waf1/Cip1 upregulation was accompanied by an incorporation of p21Waf1/Cip1 into various cyclin-CDK complexes and that the kinase activity of these complexes was increased, thus resulting in cell cycle progression. Furthermore, depletion of p21Waf1/Cip1 by antisense strategy attenuated the PKC-induced cell cycle progression. These results suggest that PKC α activity controls glioma cell cycle progression through the upregulation of p21Waf1/Cip1, which facilitates active cyclin-CDK complex formation.

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Semi-Synthetic Ingenol Derivative from Euphorbia tirucalli Inhibits Protein Kinase C Isotypes and Promotes Autophagy and S-phase Arrest on Glioma Cell Lines

Molecules ◽

10.3390/molecules24234265 ◽

2019 ◽

Vol 24 (23) ◽

pp. 4265 ◽

Cited By ~ 3

Author(s):

Silva ◽

Rosa ◽

Tansini ◽

Martinho ◽

Tanuri ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Cell Lines ◽

Glioma Cell ◽

Glioma Cells ◽

S Phase ◽

Kinase C ◽

Phase Arrest ◽

S Phase Arrest ◽

Glioma Cell Lines

The identification of signaling pathways that are involved in gliomagenesis is crucial for targeted therapy design. In this study we assessed the biological and therapeutic effect of ingenol-3-dodecanoate (IngC) on glioma. IngC exhibited dose-time-dependent cytotoxic effects on large panel of glioma cell lines (adult, pediatric cancer cells, and primary cultures), as well as, effectively reduced colonies formation. Nevertheless, it was not been able to attenuate cell migration, invasion, and promote apoptotic effects when administered alone. IngC exposure promoted S-phase arrest associated with p21CIP/WAF1 overexpression and regulated a broad range of signaling effectors related to survival and cell cycle regulation. Moreover, IngC led glioma cells to autophagy by LC3B-II accumulation and exhibited increased cytotoxic sensitivity when combined to a specific autophagic inhibitor, bafilomycin A1. In comparison with temozolomide, IngC showed a mean increase of 106-fold in efficacy, with no synergistic effect when they were both combined. When compared with a known compound of the same class, namely ingenol-3-angelate (I3A, Picato®), IngC showed a mean 9.46-fold higher efficacy. Furthermore, IngC acted as a potent inhibitor of protein kinase C (PKC) activity, an emerging therapeutic target in glioma cells, showing differential actions against various PKC isotypes. These findings identify IngC as a promising lead compound for the development of new cancer therapy and they may guide the search for additional PKC inhibitors.

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