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Post-mitotic G1 phase survivin drives mitogen-independent cell divisions of B lymphocytes

ABSTRACT: The prevailing dogma is that renewed mitogenic signaling is essential to traverse G1 phase of the cell cycle after each division. B lymphocytes undergo multiple mitotic divisions, termed clonal expansion, to expand antigen-specific cells that mediate effective immunity. We explored mechanisms by which primary murine B lymphocytes make cell division decisions. We demonstrate that commitment to DNA replication _S phase_ programs B cells to divide multiple times in the absence of overt mitogenic signaling. The extent of division is limited by cell death rather than by return to quiescence, and circumventing cell death permits up to 4 rounds of division in 72h. Mitogen-independent cell cycle progression is driven by unique S- and G2/M- like characteristics of the G1 phase of cells that have divided once, such as, large cell size, low levels of p27, phosphorylated Rb and expression of G2/M markers survivin, Cenp-A and Aim1/Aurora B. Pharmacologic inhibition of survivin blocked G1 progression in a B cell line and in primary B cells undergoing mitogen-independent division. These observations indicate that, in contrast to textbook models of the cell cycle, B cells inherit a partially active G1 phase after cell division that permits them to move quickly to the next S phase in the absence of exogenous G1 progression signals. Our studies provide direct evidence for Pardee’s hypothesis that retention of features of G2/M in post-mitotic cells could trigger a second round of cell cycle progression. We propose that these mechanisms may assist in rapid cell division without differentiation that is required for clonal expansion in response to antigens.

ORGANISM(S): Mus musculus

PROVIDER: GSE195698 | GEO | 2022/04/29

REPOSITORIES: GEO

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BW001: E2F7 represses a network of oscillating cell cycle genes to control S-phase progression

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E2F7 represses a transcriptional network of oscillating cell cycle genes to control S-phase progression.

2012-01-04 | E-GEOD-32673 | biostudies-arrayexpress

BW001

Project description:E2F transcription factors are known to be important for timely activation of G1/S and G2/M genes required for cell cycle progression, but transcriptional mechanisms for deactivation of cell cycle-regulated genes are unknown. Here, we show that E2F7 is highly expressed during mid to late S-phase, occupies promoters of G1/S-regulated genes and represses their transcription. ChIP-seq analysis revealed that E2F7 binds preferentially to genomic sites containing the TTCCCGCC motif, which closely resemble the E2F consensus site. We identified 89 target genes that carry E2F7 binding sites close to the transcriptional start site and that are directly repressed by short term induction of E2F7. Most of these target genes are known to be activated by E2Fs and are involved in DNA replication, metabolism and DNA repair. Importantly, induction of E2F7 during G0-G1/S resulted in S-phase arrest and DNA damage, whereas expression of E2F7 during G2/M failed to disturb cell cycle progression. These findings provide strong evidence that E2F7 directly controls the downswing of oscillating G1/S genes during S-phase progression. Overexpression of E2F7 was studied in a doxycyclin-inducable system. Four cellcultures were treated with and without doxycyclin and RNA was isolated to run direct comparisons on a 2-channel human expression microarray.

2012-04-30 | E-GEOD-33448 | biostudies-arrayexpress

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