Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101529


Historical Background

B-MYB is a member of the Myeloblastosis transcription factor (TF) family which is present in all vertebrates. The other members of the family are A-MYB and c-MYB. c-MYB was the first one to be discovered as a homologue of the v-MYB oncogene carried by two different avian leukemia viruses, Avian Myeloblastosis Virus (AMV) and E26 (Fig. 1) which cause acute myeloblastic leukemia and can also transform immature hematopoietic cells in culture.
B-Myb, Fig. 1

Structures of AMV v-MYB and c-MYB. This figure depicts the conserved functional domains present in c-MYB. The boxes represent the most conserved domains present among the mouse, chicken, and human proteins. In comparison to c-MYB, the AMV v-MYB protein is truncated at both amino and carboxy terminal and also has many point mutations, indicated by stars, all of which affect the transformation activity of AMVv-MYB. The EVES domain is located near the carboxy terminus and is involved in auto inhibition of c-MYB activity

A-MYB and B-MYB were discovered later via homology to c-MYB. A, B, and c-MYB are structurally very similar with nearly identical DNA binding domains (Fig. 2). In humans, B-MYB gene is located on chromosome 20q13.1.
B-Myb, Fig. 2

Structure of the MYB proteins. The three vertebrate MYB proteins have nearly identical DNA-binding domains (shown as red boxes) located near the amino-terminus. The remainder of the proteins diverges between them at other domains. There is some sequence similarity between identity of the trans activation domains of A-MYB and c-MYB (green boxes). The most weakly conserved domain is the negative regulation domain indicated by blue boxes located near the carboxy terminus

Although c-MYB was the first to be discovered, B-MYB is believed to be the ancestral progenitor of the Myeloblastosis transcription factor family. Of the three isoforms of MYB, B-MYB is most closely related to the MYB found in Caenorhabditis elegans, Drosophila melanogaster, and Sea urchins. B-MYB is also suggested to be part of evolutionary conserved protein machinery as it binds to E2F and pRB along with various other proteins in a manner similar to D.melanogaster MYB (dMYB).

Unlike A and c-MYB whose expression is tissue specific and dependent on the stage of development, B-MYB is ubiquitous and present in all rapidly proliferating cells at all stages of mammalian development and in the adult.

B-MYB in Cell Cycle Progression

A large growing body of work has investigated the key role played by B-MYB in cell cycle progression. B-MYB transcription begins in late G1 phase and is highest during S-phase (Robinson et al. 1996).

There have been several studies demonstrating that B-MYB is an E2F-regulated gene and its expression is regulated by the RB family of pocket proteins acting on the B-MYB promoter. The binding of E2F at the B-MYB promoter along with the p107 and p130 pocket proteins (RB family of proteins) represses B-MYB expression and hence inhibits cell cycle progression/control (W-FLam and JWatson 1993). High levels of B-MYB in S-phase lead to the transactivation of a number of target genes required for cell cycle progression including c-myc, DNA polymerase-α, Hsp70, cdc2, DNA topoisomerase II-α, and B-MYB itself.

B-MYB expressed in S-phase is functionally activated by phosphorylation through cyclinA/CDK2 (Saville and Watson 1998). The phosphorylation of B-MYB potentially activates B-MYB by obstructing the binding of corepressors to the B-MYB promoter thereby increasing transcriptional activity. The level of B-MYB protein is regulated by ubiquitination of phosphorylated B-MYB through the Ubiquitin ligase SKP2 followed by its proteasome-mediated degradation to restrict its presence and activity to only the S-phase of cell cycle.

Another function of B-MYB relevant to cell cycle progression is the direct link to clathrin and filamin, two important components of mitotic spindle fibers. This suggests that genome instability caused due to lack of B-MYB in zebrafish, Drosophila, or mice can be due to improper formation of spindle fibers.

DREAM complex:

As described by Sadasivam and DeCaprio, the DREAM complex is the master coordinator of cell cycle-dependent gene expression (Sadasivam and DeCaprio 2013). DREAM is a multisubunit complex formed by the assembly of p130 and p107 (RB family of proteins) with Dimerization partner (DP), E2F, and a Multivulval class B (MuvB) core complex which represses most if not all gene expression in quiescence (Litovchick et al. 2007) (Chan et al. 2014). The MuvB core complex comprises of LIN9, LIN37, LIN 52, LIN 54, and RBBP4 (Sadasivam et al. 2012). DeCaprio and colleagues have shown that in mammalian cells, the MuvB core complex dissociates from p130 and sequentially recruits B-MYB, during S phase, and FOXM1, in G2 phase, to activate mitotic gene expression (Schmit et al. 2007) (Sadasivam et al. 2012). Even though the role of the DREAM complex in cellular senescence is not fully understood, studies have shown that disorganization of the DREAM complex leads to suppression of Ras-induced senescence (Litovchick et al. 2011). The components and functions of these complexes are highly conserved in vertebrates, flies, and worms (Sadasivam and DeCaprio 2013) (Fig. 3).
B-Myb, Fig. 3

Role of the DREAM complex in cell cycle regulation: Association of MuvB complex (LIN9, LIN37, LIN52, LIN54, and RBBP4) with different factors at different phases in cell cycle regulates gene expression during the cell cycle. In quiescence, when cells are arrested MuvB binds to p130/p107, E2F4, and DP to form the DREAM complex, which inhibits all cell cycle-dependent gene expression and hence arrest cell growth. When cells exit quiescence, p130 dissociates from MuvB and E2F allowing activator E2Fs to activate genes required for progression through S phase. MuvB binds to B-MYB in S phase to regulate late S phase genes. In G2 phase, MuvB-B-MYB complex recruits FOXM1 followed by proteasomal degradation of B-MYB. Active FOXM1 remains bound to MuvB and regulates the expression of genes required in G2-M transition. Figure from (Mowla et al. 2014)

There are a number of published studies describing the involvement of B-MYB in carcinogenesis. This is not surprising as B-MYB plays a crucial role in cell cycle progression and its overexpression is associated with several different types of cancer and aggressive tumor growth. Cytogenetic analysis of many types of cancer has detected amplification of chromosome 20q13, the chromosomal location of B-MYB.

Role of B-MYB in Cellular Senescence and Aging

Cellular senescence is defined as a program of stable growth arrest which normal cells undergo after a finite number of divisions called the Hayflick limit (Hayflick and Moorhead 1961). As B-MYB is required for and promotes cell cycle progression, it indirectly suggested that B-MYB might have a role in preventing senescence. This was demonstrated by studies in which B-MYB inhibition by RNA interference was shown to induce senescence. (Johung et al. 2007).

A considerable amount of work along with previous research in our lab has shown that B-MYB is one of the most highly downregulated TFs upon senescence growth arrest and the downregulation was reversed when senescence was bypassed upon inactivation of the p16-pRB and p53-p21 tumor suppressor pathways, two key pathways known to have role in establishing and maintaining senescence. Ongoing research in our lab has found that ectopic expression of B-MYB bypasses senescence in the conditionally immortal human mammary fibroblasts (HMF3); these cells can be induced to undergo senescence synchronously by altering the growth conditions. This suggests that loss of B-MYB expression may have causative role in senescence.

Senescence can be triggered in response to a variety of intrinsic and extrinsic stimuli including: progressive telomere shortening, changes in telomeric structure, oxidative stress, oncogene overexpression, loss of cell contact, and DNA damage. Senescence growth arrest is induced and maintained mainly via p53-p21 and p16-pRB tumor suppressor pathways. There is evidence suggesting that B-MYB can suppress senescence by inhibiting the p16-pRB pathway (Huang et al. 2011). They showed that B-MYB is a transcriptional repressor of the cell cycle inhibitor, p16INK4A, suggesting that inhibition of p16INK4A by B-MYB leads to cyclinD/CDK4,6 activation which subsequently phosphorylates and inactivates pRB leading to cell proliferation thereby overcoming cell cycle arrest.

B-MYB is repressed both during quiescence and senescent growth arrest by RB-mediated repression. In quiescence the RB family members p107 and p130 along with E2F4 bind to the E2F site on the B-MYB promoter to form the repressive DREAM complex to repress B-MYB transcription, thereby promoting cell cycle arrest. However, in senescence RB-mediated repression of B-MYB is stronger due to the destabilization of B-MYB mRNA by RB-mediated overexpression of the miR29 and miR30 family of micro RNAs (miRNAs). This suggests that the level of B-MYB might be very important and act as a deciding factor between cell proliferation, cell senescence, and quiescence. Thus, moderately low levels of B-MYB lead to quiescence whereas extremely low levels of B-MYB, due to miRNA-mediated degradation, manifest senescence whereas high levels of B-MYB lead to cell cycle progression.

B-MYB has recently emerged as a candidate that plays a role in attenuating senescence and as a potential candidate for regulating entry into senescence. It has vital antisenescence qualities due to its role in cell proliferation and growth. Loss of B-MYB expression has an important role in causing senescence growth arrest as silencing of B-MYB expression in primary human foreskin fibroblasts induces senescence (Johung et al. 2007), and overexpression of B-MYB can rescue Ras-induced premature senescence in rodent cells (Masselink et al. 2001).

Other Key Roles of MYB

Cell Death

A number of studies have found that B-MYB plays a role in cell death and have suggested that B-MYB promotes cell cycle progression through the overexpression of antiapoptotic genes namely clusterin, survivin, and BCL2.


Of the three members of the Myeloblastosis family of TFs, B-MYB is the only one found to be present in embryonic stem (ES) cells. It has a critical role in early embryonic development as mice lacking B-MYB die at a very early stage of development as a consequence of defects in formation of inner cell mass in the blastocyst (Tanaka et al. 1999). Along with maintaining the self-renewal capacity of ES cells (Zhan et al. 2012), Tarasov et al. have shown that knockdown of B-MYB in murine ES cells leads to delayed transit through G2/M, severe mitotic spindle, and centrosome defects leading to polyploidy. Loss of B-MYB also leads to a reduction in Oct4 expression which eventually leads to ES cell differentiation as differentiated cells have tight cell cycle checkpoint controls capable of identifying chromosomal abnormalities and promoting apoptosis. (Tarasov et al. 2008).

Nutrient and Metabolic Signaling

Recently, there has been increasing interest in the role of B-MYB in nutrient and metabolic signaling and linking it to antiaging signaling. Numerous studies have attempted to explain the increase in lifespan of organisms by inhibition of mechanistic target of rapamycin (mTOR) pathway by rapamycin or through dietary restriction. A connection between B-MYB and inhibition of mTOR by rapamycin can be explained by the reduction of oxidative stress and premature senescence which results in an increase in replicative life span by rapamycin thereby connecting this pathway to cell senescence and hence to B-MYB (Li et al. 2012).

There is further evidence suggesting that mTOR can affect the B-MYB pathway in Arabidopsis (Ye et al. 2012). Although until now no evidence has been discovered in mammals this suggests there may be a potential link (Fig. 4).
B-Myb, Fig. 4

Schematic representation of the pathways which relate B-MYB to cellular senescence and aging. This shows how loss of B-MYB expression can lead to senescence growth arrest and therefore assist in aging. It also demonstrates how DNA damage, dietary restriction, and oxidative/oncogenic stress may lead to senescence growth arrest and aging through B-MYB. Figure from (Mowla et al. 2014)


B-MYB plays a unique role in maintaining cell homeostasis thereby playing a critical role in a variety of biological processes. Mice lacking B-MYB die very early in development as a consequence of the impaired inner cell mass formation in the blastocyst suggesting a critical role in development. Although B-MYB plays many roles, its key role is in cell cycle progression. DeCaprio and colleagues have shown that in mammalian cells, the MuvB core complex dissociates from p130 and sequentially recruits B-MYB, during S phase, and FOXM1, in G2 phase, to activate mitotic gene expression (Schmit et al. 2007; Sadasivam et al. 2012).

Because of the oncogenic discovery of c-MYB the literature surrounding MYB family of proteins is always skewed towards their oncogenic potential because of which there are only a few studies in literature that deal with the loss of B-MYB in senescence growth arrest. A considerable body of data has shown that repression of B-MYB expression can prevent proliferation in both normal and tumor cells. As B-MYB is suggested to have causative role in senescence, more research is needed to better understand mechanisms on how B-MYB blocks senescence and is integrated into senescence-inducing pathways.

Levels of B-MYB expression maintained and regulated by p53-p21 and p16-pRB pathways critically determine if a particular cell will undergo proliferation, quiescence, or apoptosis. This poses the further question: Can levels of B-MYB itself be used as an informative biomarker?

Studies have shown that removal of senescent cells can prevent or delay age related tissue dysfunction and extend health span (Baker et al. 2011). Although there is much work on the importance of DREAM complex in quiescence and its role in repressing cell cycle-dependent gene expression, very little research has focused on role of DREAM complex in senescence. So it is necessary to further examine the role of the DREAM complex in cellular senescence.

Evidence in the literature suggests that there may be a link between B-MYB and FOXM1. They have common downstream targets such as CCNB1, PLK1, and AURK1, which are required for progression into mitosis. Their levels are also repressed during G0, and their activities are regulated by cell cycle-dependent phosphorylation. They also undergo cell cycle-dependent ubiquitin-mediated proteasome degradation. Further research is required to establish a potential link between B-MYB and FOXM1.

It is recommended that further research be undertaken to determine the role of B-MYB in preventing senescence and identifying downstream targets, particularly those targets that may be involved in the stability of senescence arrest. These targets will represent novel, important and direct targets for developing new therapies that promote healthier aging and increase vitality of the older population through stimulating regeneration, repair, and wound healing, while retaining the tumor suppressor properties of senescence, if possible. These targets will also be new therapeutic cancer targets, for developing small molecule inhibitors and activators aimed at inducing senescence in tumors. Even though targeting TFs is challenging, it may be possible to develop therapeutics targeting B-MYB itself because of its extensive posttranslational modifications.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Neurodegenerative DiseaseInstitute of Neurology, University College LondonLondonUK