c-Myc enhances protein synthesis and cell size during B lymphocyte development

Abstract

It has been known for some time that cell cycle progression is tightly coupled to an accumulation of cell mass (i.e., cell growth) (1). However, the molecules that control cell growth and the mechanisms through which growth and proliferation are coupled are only beginning to be defined (2). One group of genes whose function may be important for both growth and proliferation is the members of the myc protooncogene family, c-, N-, and L-myc.The proteins encoded by myc family genes are members of the basic-helix-loop-helix-zipper (bHLHZ) class of transcription factors. Dimerization of Myc protein with its obligate partner Max results in formation of a heterodimer with sequence-specific DNA-binding activity (3, 4). Myc-Max heterodimers appear to activate transcription when bound to promoter-proximal sites on DNA (5, 6). In addition, Myc is known to repress transcription of specific genes (7). Although max expression is constitutive, myc expression is highly regulated at transcriptional, posttranscriptional, translational, and posttranslational levels (8-11). In general, c-Myc expression is associated with proliferation and is down-regulated in quiescent and differentiated cells. After serum or mitogen stimulation of quiescent cells, myc levels peak within several hours, followed by a decline to a low basal level maintained by synthesis and degradation (12-15) and dependent on the continued presence of growth factors (16). Ectopic expression of c-myc in normally quiescent cells can potentiate entry into S phase, and cells that constitutively express myc have reduced growth factor requirements, shortened doubling times, and in some cases have circumvented cell cycle exit (17)(18)(19)(20). Conversely, failure to induce c-myc in response to mitogenic signaling abrogates cell cycle progression (21) whereas a fibroblast cell line bearing targeted homozygous c-myc deletions has significantly decreased proliferation rates and lengthened G 1 and G 2 phases (22). These observations together have led to the notion that Myc-Max functions to modulate expression of genes promoting cell cycle progression (for reviews, see refs. 23-25).Deregulated expression of myc family genes, through gene amplification, viral promoter insertion, chromosomal translocation, or promoter mutation, has long been associated with neoplastic disease in a wide range of vertebrates including humans (for reviews, see refs. 26-29). Among the most striking examples of the importance of myc in cancer development are the chromosomal translocations involving c-myc and Ig heavy-or light-chain loci that are characteristic of Burkitt's lymphoma in humans and plasmacytomas in mice and rats. A powerful model system for B cell lymphoma (E-myc mice) entails expression of c-myc in murine lymphoid cells as a transgene under control of the Ig heavy-chain enhancer (30) (for review see ref. 31). E-myc mice develop clonal B cell lymphomas with a mean latency of 12-16 wk of age. Before transformation, B cell progenitors appear relatively normal in these mice. However, an exp...

Glycolytic rate and lymphomagenesis depend on PARP14, an ADP ribosyltransferase of the B aggressive lymphoma (BAL) family

“…In addition, it is intriguing that bone marrow pre-B cells appeared more resistant to inhibition of glycolysis than their more mature IgM + progeny (45). In any case, the emergence of lymphoma is thought to be due in part to the accumulation of an expanded pre-B population in Eμ-myc mice (27,28). Thus, the combined changes may account for the contribution of this BAL-family ADP ribosyltransferase to Mycinduced lymphomagenesis.…”

“…Of note, we found that PARP14 is crucial for Eμ-myc cells fully to increase their glycolysis and size. Thus, the proliferative drive and faster protein synthesis forced by sustained c-Myc overexpression (27,28) must contend with a restriction on the rate of glycolysis when PARP14 is absent. Rapid engulfment of apoptotic cells in vivo precludes accurately measuring rates of apoptosis in situ.…”

“…S6). Myc expression in this system forces increased cell size on B-lineage cells (27,28), but the absence of PARP14 from the B220 + population countered this in each subset ( Fig. 6C and Table S2).…”

Cyclin a but not cyclin D1 is essential for c‐myc‐modulated cell‐cycle progression

“…To the opposite, downregulation of c-myc expression in A549 cells retarded cell growth and caused G1 phase arrest. cmyc enhances cell size during B lymphocyte development and can enhances cell growth to levels required for unrestrained cell division (Iritani and Eisenman, 1999). c-myc is involved in the regulation of cell growth via increase cell size (Johnston et al, 1999;Schuhmacher et al, 1999), but could not override a size control on S phase entry (Neufeld and Edgar, 1998).…”

c-myc Is Required for Osteoclast Differentiation

“…In fact, Myc overexpression leads to reduced requirements for growth factors, blocks exit from cell cycle, and accelerates cell division. (12)(13)(14) Myc levels diminish during terminal differentiation of many cell types and its overexpression inhibits differentiation. However, recent data suggest that Myc also may play a role in moving cells along during hematopoietic and epidermal differentiation.…”