Review
Myc and cell cycle control

https://doi.org/10.1016/j.bbagrm.2014.03.013Get rights and content

Highlights

  • Myc can stimulate cell cycle progression through several parallel mechanisms.

  • Many of the pivotal positive cell cycle regulators are encoded by Myc target genes.

  • Myc induces the expression of some cyclins, Cdks and proteins involved in replication.

  • Myc counteracts the activity of p21 and p27 cell cycle inhibitors.

Abstract

Soon after the discovery of the Myc gene (c-Myc), it became clear that Myc expression levels tightly correlate to cell proliferation. The entry in cell cycle of quiescent cells upon Myc enforced expression has been described in many models. Also, the downregulation or inactivation of Myc results in the impairment of cell cycle progression. Given the frequent deregulation of Myc oncogene in human cancer it is important to dissect out the mechanisms underlying the role of Myc on cell cycle control. Several parallel mechanisms account for Myc-mediated stimulation of the cell cycle. First, most of the critical positive cell cycle regulators are encoded by genes induced by Myc. These Myc target genes include Cdks, cyclins and E2F transcription factors. Apart from its direct effects on the transcription, Myc is able to hyperactivate cyclin/Cdk complexes through the induction of Cdk activating kinase (CAK) and Cdc25 phosphatases. Moreover, Myc antagonizes the activity of cell cycle inhibitors as p21 and p27 through different mechanisms. Thus, Myc is able to block p21 transcription or to induce Skp2, a protein involved in p27 degradation. Finally, Myc induces DNA replication by binding to replication origins and by upregulating genes encoding proteins required for replication initiation. Myc also regulates genes involved in the mitotic control. A promising approach to treat tumors with deregulated Myc is the synthetic lethality based on the inhibition of Cdks. Thus, the knowledge of the Myc-dependent cell cycle regulatory mechanisms will help to discover new therapeutic approaches directed against malignancies with deregulated Myc. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology.

Section snippets

Introduction. Overview of cell cycle regulation

Progression through the cell cycle phases (G1, S, G2 and M) 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 Cdk to be active. To date, there are 21 genes encoding Cdks and 29 genes encoding cyclins in the human genome [1], [2]. Of these, Cdk1, 2, 4 and 6 and A, B, E, D-type cyclins are identified as the major

Myc levels correlate with cell proliferation

Soon after the discovery of Myc gene it was recognized that Myc mRNA and protein expression closely correlated with cell proliferation rates. This was first reported at the mRNA level in quiescent lymphocytes and rodent fibroblasts in which Myc mRNA underwent a rapid induction within 2 h after stimulation with mitogenic lectins [38], [39], [40]. Thus, Myc gene was dubbed as “immediate early” response gene. Later on, Myc upregulation was also described in response to growth factors, due to both

Myc overexpression induces cell cycle progression in quiescent cells

In agreement with the tight correlation between proliferation rates and Myc levels, the enforced Myc expression in quiescent cells is sufficient to mediate cell cycle entry, whereas inhibition of Myc expression causes cycling cells to withdraw from the cell cycle. This was observed in early experiments where Myc protein was transfected or microinjected into mouse fibroblasts [63], [64]. High Myc levels achieved upon transfection or retroviral transduction in cycling mammalian cells result in a

Myc downregulation impairs cell cycle progression and mitogenic response

Consistently with the enhanced proliferation observed upon Myc overexpression, the downregulation or biochemical inactivation of Myc results in defective cell cycle re-entry of quiescent cells. Thus, Myc antisense oligonucleotides prevent S-phase entry in human lymphoid and myeloid cells [74], [75]. Similarly, transfection and microinjection experiments also show that dominant negative Myc mutants (with deletions of the N-terminal transactivation domain) impair the DNA synthesis induced by

Myc target genes related to cell cycle control

Given the Myc effects on proliferation previously mentioned, it is not surprising that cell cycle related genes (cyclin D2, cyclin E1, Cdk4, Cdc25A, E2F1) were among the first described as “Myc target genes” (reviewed in [32], [93], [94]). Prominent examples of these Myc target genes as revealed in these and other studies, as well as the model where the effect is observed, are summarized in Table 1. The Table also shows the binding of Myc to the corresponding gene promoter as demonstrated by

Myc induces Cdks activity

Myc-induced cell proliferation is generally associated with an increase in Cdk2, Cdk4 and Cdk6 activities to regulate G1/S-phase progression [89], [133], [134], [135] (Fig. 1). Importantly, Myc is able to augment the levels of active cyclin/Cdk complexes not only through the transactivation of the cyclin and/or Cdk genes but also by induction of Cdk activating kinase (CAK) or phosphatases (Cdc25 proteins) and/or repression of a Cdk inhibitory kinase (Wee1). These mechanisms are described below.

Myc and p21CIP1

As mentioned before, Myc represses the cyclin-dependent kinase inhibitor p21CIP1/WAF1 (p21 hereafter). One of the first evidences came from human immortalized keratinocyte cells stably expressing Myc, where Myc inhibited TGFβ-mediated repression of cell-cycle progression abolishing the induction of p21 expression [167]. Several mechanisms are used by Myc to repress p21 and are summarized in Fig. 2. The most studied mechanism for Myc-mediated repression of p21 is through the initiator-binding

Myc and p27KIP1

One of the most important targets of Myc in cell proliferation is the Cdk inhibitor p27. Myc accelerates cell proliferation rates, at least in part, through its ability to antagonize p27 function as Cdk inhibitor [179], [180]. Accordingly, Myc-deficient cells show increased p27 protein levels [89], [91]. This is accomplished by several parallel mechanisms, summarized in Fig. 3: (i) Myc suppresses p27 expression at the transcriptional level in lymphoid and breast cancer cells [181], [182] (

Myc, DNA replication and mitosis

Myc induces genes directly related to DNA replication. The origin recognition complex (ORC) is a highly conserved six subunits protein complex essential for the initiation of the DNA replication in eukaryotic cells. A number of ORC genes as ORC1, ORC2, ORC4 and ORC5 have been identified as Myc targets in mouse fibroblasts and human B cells [101], [103]. The gene encoding for Cdc6 (Cell Division Cycle 6), a protein required for the initiation of replication, has also been found to be a Myc

Conclusion and remarks

We have reviewed here the many functions of Myc related to the cell cycle regulation. From the pioneering studies in the 1980s to the genome-wide studies today, the general picture shows that control of cell proliferation is one of the major roles of Myc in cell biology. The bulk of the data shows that Myc overexpression stimulates whereas Myc downregulation inhibits cell cycle progression. Several mechanisms by which Myc influences the cell cycle have been elucidated. Most of them are related

Acknowledgements

The work in the laboratory of the authors is funded by grants SAF11-23796 from Spanish Ministry of Industry and Innovation, and ISCIII-RETIC RD12/0036/0033 from Spanish Ministry of Health to JL, and FIS 11/00397 to MDD. GB is recipient of a fellowship form the FPI Program. The funding was co-sponsored by the European Union FEDER program. We apologize to colleagues whose work has not been cited in the form of their original papers but in reviews or by unintentional omission.

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