Evidence that phosphorylation by the mitotic kinase Cdk1 promotes ICER monoubiquitination and nuclear delocalization

Mémin, Elisabeth; Genzale, Megan; Crow, Marni S.; Molina, Carlos A.

doi:10.1016/j.yexcr.2011.07.001

Cited by 7 publications

(9 citation statements)

References 41 publications

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“…The initially described post-transcriptional regulation was polyubiquitination, which guided ICER to proteasome degradation (39). Recently, phosphorylation with the mitotic kinase CDK1 was also described, resulting in ICER export to the cytoplasm (26).When ICER is overexpressed in cell lines, it is usually phosphorylated and therefore not active as a transcription factor. Cyclin D 1 was not successfully silenced when intact ICER was used for the transfections, but when lysines at the phosphorylation sites were changed to arginines, repression was achieved (26).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, phosphorylation with the mitotic kinase CDK1 was also described, resulting in ICER export to the cytoplasm (26).When ICER is overexpressed in cell lines, it is usually phosphorylated and therefore not active as a transcription factor. Cyclin D 1 was not successfully silenced when intact ICER was used for the transfections, but when lysines at the phosphorylation sites were changed to arginines, repression was achieved (26). In accordance with this, we have shown that the majority of the overexpressed ICER in Hepa 1-6 cells ends in the cytoplasm and not in the nucleus (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We could not show the direct inhibition of Per1 with ICER transfections (data not shown). According to recent literature, ICER introduced into immortal cells by transient transfection is immediately phosphorylated, which is a signal for its transport to the cytoplasm (26). To evaluate this result for Hepa 1-6 cells, we measured ICER proteins after transfection (Fig.…”

Section: Icer Represses Transcription Of Per1 Through Binding To the mentioning

confidence: 99%

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Inducible cAMP Early Repressor Regulates the Period 1 Gene of the Hepatic and Adrenal Clocks

Zmrzljak

Korenčič

Košir

et al. 2013

Journal of Biological Chemistry

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Background:We investigated the role of cAMP signaling (Crem and its splice variant Icer) in liver and adrenal clocks. Results: cAMP signaling fine-tunes adrenal clock genes, whereas the hepatic effect is minimal. ICER regulates Per1 by binding to its promoter. Conclusion: Icer fine-tunes clock gene expression in the absence of light and feeding cues. Significance: ICER is a circadian signal mediator.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Icer Represses Transcription Of Per1 Through Binding To the mentioning

confidence: 99%

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Inducible cAMP Early Repressor Regulates the Period 1 Gene of the Hepatic and Adrenal Clocks

Zmrzljak

Korenčič

Košir

et al. 2013

Journal of Biological Chemistry

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“…Interestingly, Mémin et al recently showed that CDK1 phosphorylated the ICER (inducible cyclic AMP early repressor) splice variant of CREM on Ser-35, which is analogous to CREB Ser-271 (52). Thus, mitotic phosphorylation of positionally conserved CDK1 sites appears to be common to all members of the CREB/ATF family of transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent Kinase 1-dependent Phosphorylation of cAMP Response Element-binding Protein Decreases Chromatin Occupancy

Trinh

Kim

Chang

et al. 2013

Journal of Biological Chemistry

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Background: cAMP response element-binding protein (CREB) is a transcriptional regulator that undergoes complex phosphoregulation in response many physiologic stimuli. Results: Ser-270/Ser-271 are identified as mitotically regulated phosphorylation sites that diminish CREB DNA binding activity. Conclusion: Carboxyl-terminal phosphorylation of CREB promotes its chromatin eviction during mitosis. Significance: CDK1-mediated chromatin eviction may serve as a global mechanism to mediate transcriptional inhibition observed during mitosis.

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“…Typically described as having an inactivating genetic mutation [1], there is a growing understanding of the tumor suppressor protein displaying a loss‐of‐function while having an intact gene. This epigenetic inactivation has been recognized in several proteins [2–8]; where the loss of function is a result of protein degradation or translocation.…”

Section: Introductionmentioning

confidence: 99%

Ras‐induced melanoma transformation is associated with the proteasomal degradation of the transcriptional repressor ICER

Healey¹,

Crow

Molina

2012

Molecular Carcinogenesis

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Activation of the mitogen-activated protein kinase (MAPK) pathway targets the putative tumor suppressor protein inducible cAMP early repressor (ICER) to ubiquitin-mediated proteasomal degradation [Yehia et al. JBC 2001; 276: 35272-35279]. We demonstrate that ICER proteasomal degradation is implicated in Ras/MAPK-mediated melanoma tumorigenesis. In a system using Tyr/Tet-Ras INK4a-/- transgenic mice and melanoma cells in culture termed R545 cells isolated from Tyr/Tet-Ras INK4a-/- mice [Chin et al. Nature 1999; 400: 468-472], melanoma genesis and melanoma maintenance is strictly dependent upon expression of H-RasV12G. We found that ICER protein was not expressed during melanoma genesis but was strongly expressed in regressing melanomas. Similarly in R545 cells, ICER protein expression was negatively regulated by H-RasV12G. The expression of ICER mRNA was not affected by H-RasV12G expression, suggesting that ICER regulation was post-translational. Indeed, pharmacological inhibition of Ras activity or the proteasome abolished the degradation of ICER caused by H-RasV12G expression indicating that RAS oncogene regulates the expression of ICER protein by targeting ICER to proteasomal degradation. By engineering clones of R545 melanoma cells stably transfected with ICER we were able to determine the prerequisite for Ras-induced tumorigenesis. The reconstitution of physiological levels of ICER showed a significant decrease in cell growth, as well as inhibition of anchorage-independent cell growth and tumorigenicity in nude mice. ICER was found to efficiently repress the expression of cyclin D1 in R545 cells due to the binding of ICER to the CRE in the cyclin D1 promoter. Taken together, we postulate that ICER protein might be targeted to degradation in human tumors where Ras is mutated.

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Evidence that phosphorylation by the mitotic kinase Cdk1 promotes ICER monoubiquitination and nuclear delocalization

Cited by 7 publications

References 41 publications

Inducible cAMP Early Repressor Regulates the Period 1 Gene of the Hepatic and Adrenal Clocks

Inducible cAMP Early Repressor Regulates the Period 1 Gene of the Hepatic and Adrenal Clocks

Cyclin-dependent Kinase 1-dependent Phosphorylation of cAMP Response Element-binding Protein Decreases Chromatin Occupancy

Ras‐induced melanoma transformation is associated with the proteasomal degradation of the transcriptional repressor ICER

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