Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewMyc and cell cycle control☆
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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This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology.