The art of geology (E. M.. Moore and F. M. Wahl [eds.]

Molenaar, Dee

doi:10.4319/lo.1989.34.2.0492

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“…This would be the case of Myc [42]. It has been previously identified the chemical inhibition of Cdk1 and Cdk2 to be synthetic-lethal with Myc or N-Myc overexpression [38, 39,43]. As it is well known the apoptotic effect of Myc when cells are exposed to suboptimal growth conditions [44] thus it is conceivable that inhibition of Cdk1 would result in elevated p27 and thus an enhanced apoptotic effect of Myc.…”

Section: Discussionmentioning

confidence: 99%

Myc stimulates cell cycle progression through the activation of Cdk1 and phosphorylation of p27

León

García-Gutiérrez

Bretones

et al. 2018

Preprint

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blurb: Myc antagonizes p27 activity in cancer. Myc activates Cdk1 to phosphorylate p27, marking p27 for degradation. This depends on Myc-mediated cyclin A and B induction. Cdk1 inhibition is sufficient for a synthetic lethal interaction with Myc Running Title: Myc activates Cdk1 to phosphorylate p27 ABSTRACT Cell cycle stimulation is a major transforming mechanism of Myc oncoprotein. This is achieved through at least three concomitant mechanisms: upregulation of cyclins and Cdks, downregulation of Cdk inhibitors p15 and p21 and the degradation of p27. The Myc-p27 antagonism has been shown to be relevant in human cancer. To be degraded, p27 must be phosphorylated at Thr-187 to be recognized by Skp2, a component of the ubiquitination complex. We previously described that Myc induces Skp2 expression. Here we show that not only Cdk2 but Cdk1 phosphorylates p27 at the Thr187, which was previously unreported. Moreover, Myc induced p27 degradation in murine fibroblasts through Cdk1 activation, which was achieved by Myc-dependent cyclin A and B induction. In the absence of Cdk2, p27 phosphorylation at Thr-187 was mainly carried out by cyclin A2-Cdk1 and cyclin B1-Cdk1. We also show that Cdk1 inhibition was sufficient for the synthetic lethal interaction with Myc. This result is relevant because Cdk1 is the only Cdk strictly required for cell cycle and the reported synthetic lethal interaction between Cdk1 and Myc. Progression through the cell cycle phases is under the control of a family of serine/threonine protein kinases. These kinases are heterodimers consisting of a catalytic subunit, the cyclin-dependent protein kinase (Cdk) and a regulatory subunit, the cyclin, required for the Cdk to be active. Although Cdk and cyclin are large protein families, Cdk1, 2, 4 and 6 and A, B, E, D-type cyclins are identified as the major regulators of the cell cycle [1]. Systematic knockout of Cdk loci in the mouse germline has shown that Cdk2 [2, 3], Cdk4 [4,5] and Cdk6 [6] are not essential for cell cycle progression of most cell types, although loss of each of these Cdks results in particular developmental defects. Moreover, concomitant loss of the genes of interphase Cdk does not result in a general disturbance of the cell cycle in most cell types, being Cdk1 alone sufficient to drive the cell cycle [1,7].Myc (also called c-Myc) is an oncogenic transcription factor of the helix-loop-helix/leucine zipper protein family. Activation of transcription by Myc depends on formation of heterodimeric complexes with Max proteins. Myc-Max heterodimers bind to DNA sequences called E-boxes in the regulatory regions of its targets genes and recruit transcriptional coactivators, albeit Myc has also the ability to repress genes through less known mechanisms (for reviews see [8][9][10]). Myc is found deregulated in nearly half of human solid tumors and leukemia, and appears frequently associated with tumor progression [11][12][13].One of the best characterized functions of the transcription factor Myc is its potent ability to induce cell proliferat...

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Section: Discussionmentioning

confidence: 99%