Abstract
Deregulated expression of the Myc family of transcription factors (c-, N-, and L-myc) contributes to the development of many cancers by a mechanism believed to involve the stimulation of cell proliferation and inhibition of differentiation. However, using B cell-specific c-/N-myc double-knockout mice and Eμ-myc transgenic mice bred onto genetic backgrounds (recombinase- activating gene 2-/- and Btk-/- Tec-/-) whereby B cell development is arrested, we show that Myc is necessary to stimulate both proliferation and differentiation in primary B cells. Moreover, Myc expression results in sustained increases in intracellular Ca2+ ([Ca 2+]i), which is required for Myc to stimulate B cell proliferation and differentiation. The increase in [Ca2+]i correlates with constitutive nuclear factor of activated T cells (NFAT) nuclear translocation, reduced Ca2+ efflux, and decreased expression of the plasma membrane Ca2+-adenosine triphosphatase (PMCA) efflux pump. Our findings demonstrate a revised model whereby Myc promotes both proliferation and differentiation, in part by a remarkable mechanism whereby Myc amplifies Ca2+ signals, thereby enabling the concurrent expression of Myc- and Ca2+-regulated target genes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 717-731 |
| Number of pages | 15 |
| Journal | Journal of Cell Biology |
| Volume | 179 |
| Issue number | 4 |
| DOIs | |
| State | Published - Nov 19 2007 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cell Biology
Cite this
Myc stimulates B lymphocyte differentiation and amplifies calcium signaling. / Habib, Tania; Park, Heon; Tsang, Mark; De Alborán, Ignacio Moreno; Nicks, Andrea; Wilson, Leslie; Knoepfler, Paul S; Andrews, Sarah; Rawlings, David J.; Eisenman, Robert N.; Iritani, Brian M.
In: Journal of Cell Biology, Vol. 179, No. 4, 19.11.2007, p. 717-731.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Myc stimulates B lymphocyte differentiation and amplifies calcium signaling
AU - Habib, Tania
AU - Park, Heon
AU - Tsang, Mark
AU - De Alborán, Ignacio Moreno
AU - Nicks, Andrea
AU - Wilson, Leslie
AU - Knoepfler, Paul S
AU - Andrews, Sarah
AU - Rawlings, David J.
AU - Eisenman, Robert N.
AU - Iritani, Brian M.
PY - 2007/11/19
Y1 - 2007/11/19
N2 - Deregulated expression of the Myc family of transcription factors (c-, N-, and L-myc) contributes to the development of many cancers by a mechanism believed to involve the stimulation of cell proliferation and inhibition of differentiation. However, using B cell-specific c-/N-myc double-knockout mice and Eμ-myc transgenic mice bred onto genetic backgrounds (recombinase- activating gene 2-/- and Btk-/- Tec-/-) whereby B cell development is arrested, we show that Myc is necessary to stimulate both proliferation and differentiation in primary B cells. Moreover, Myc expression results in sustained increases in intracellular Ca2+ ([Ca 2+]i), which is required for Myc to stimulate B cell proliferation and differentiation. The increase in [Ca2+]i correlates with constitutive nuclear factor of activated T cells (NFAT) nuclear translocation, reduced Ca2+ efflux, and decreased expression of the plasma membrane Ca2+-adenosine triphosphatase (PMCA) efflux pump. Our findings demonstrate a revised model whereby Myc promotes both proliferation and differentiation, in part by a remarkable mechanism whereby Myc amplifies Ca2+ signals, thereby enabling the concurrent expression of Myc- and Ca2+-regulated target genes.
AB - Deregulated expression of the Myc family of transcription factors (c-, N-, and L-myc) contributes to the development of many cancers by a mechanism believed to involve the stimulation of cell proliferation and inhibition of differentiation. However, using B cell-specific c-/N-myc double-knockout mice and Eμ-myc transgenic mice bred onto genetic backgrounds (recombinase- activating gene 2-/- and Btk-/- Tec-/-) whereby B cell development is arrested, we show that Myc is necessary to stimulate both proliferation and differentiation in primary B cells. Moreover, Myc expression results in sustained increases in intracellular Ca2+ ([Ca 2+]i), which is required for Myc to stimulate B cell proliferation and differentiation. The increase in [Ca2+]i correlates with constitutive nuclear factor of activated T cells (NFAT) nuclear translocation, reduced Ca2+ efflux, and decreased expression of the plasma membrane Ca2+-adenosine triphosphatase (PMCA) efflux pump. Our findings demonstrate a revised model whereby Myc promotes both proliferation and differentiation, in part by a remarkable mechanism whereby Myc amplifies Ca2+ signals, thereby enabling the concurrent expression of Myc- and Ca2+-regulated target genes.
UR - http://www.scopus.com/inward/record.url?scp=36349002340&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36349002340&partnerID=8YFLogxK
U2 - 10.1083/jcb.200704173
DO - 10.1083/jcb.200704173
M3 - Article
C2 - 17998397
AN - SCOPUS:36349002340
VL - 179
SP - 717
EP - 731
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 4
ER -