Myc and cell cycle control

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.

MICAL1 facilitates breast cancer cell proliferation via ROS‐sensitive ERK/cyclin D pathway

“…MAPKs are highly conserved kinases that are critical for communicate signals from cell surface to DNA in the nucleus. Among the members of the MAPK family, extracellular signal‐regulated protein kinase (ERK) can alter the level and activity of transcription factor c‐myc, leading to changes in cyclin D transcription that are mainly responsible for cell cycle 27. Phosphorylation of ERK and its translocation to nucleus by ROS have been proven to be an important mechanism to mediate breast cancer cell migration by LPA 28.…”

Direct neuronal reprogramming: learning from and for development

“…Cell cycle and Myc expression are both strongly linked to the metabolic and redox state of cells (Bretones et al, 2015). In nervous system development, however, very little is known about the metabolic changes that occur during the transition from neural stem and progenitor cells to neurons or distinct glial cells (Diaz-Castro et al, 2015).…”

MYC as therapeutic target in leukemia and lymphoma

“…It is still unclear to what extent MYC contributes to the overexpression of these new "invaded" genes, 13,14 but it is established that upon MYC induction or activation, the expression of a series of "MYC target genes" become overexpressed with respect to most other genes of the cell, whereas others (eg, the genes of cell cycle inhibitors CDKN1A and CDKN2B) are downregulated. 14,15 In agreement with the large number of regulated genes, overexpression of MYC impinges on a series of functions that confer ample competitive advantages to the cell, such as cell cycle stimulation, nucleotide biosynthesis, differentiation impairment, energy production, protein synthesis and ribosome genesis, genomic instability, immortalization, and telomere maintenance or block of differentiation. 3,7,8,15,16 All these combined functions contribute to -or trigger -the development of hematological neoplasia ( Figure 1).…”

“…14,15 In agreement with the large number of regulated genes, overexpression of MYC impinges on a series of functions that confer ample competitive advantages to the cell, such as cell cycle stimulation, nucleotide biosynthesis, differentiation impairment, energy production, protein synthesis and ribosome genesis, genomic instability, immortalization, and telomere maintenance or block of differentiation. 3,7,8,15,16 All these combined functions contribute to -or trigger -the development of hematological neoplasia ( Figure 1). Indeed, MYC oncogene was originally discovered as the oncogene carried by retroviruses that induced a myeloid neoplasm in chicken, ie, myelocytomatosis, and MYC was named after this tumor.…”