MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation

Abstract

The regulation of cell mass (cell growth) is often tightly coupled to the cell division cycle (cell proliferation). Ribosome biogenesis and the control of rDNA transcription through RNA polymerase I are known to be critical determinants of cell growth. Here we show that granulocytic cells deficient in the c‐MYC antagonist MAD1 display increased cell volume, rDNA transcription and protein synthesis. MAD1 repressed and c‐MYC activated rDNA transcription in nuclear run‐on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c‐MYC activated transcription from the UBF promoter. Using siRNA, UBF was shown to be required for c‐MYC‐induced rDNA transcription. These data demonstrate that MAD1 and c‐MYC reciprocally regulate rDNA transcription, providing a mechanism for coordination of ribosome biogenesis and cell growth under conditions of sustained growth inhibition such as granulocyte differentiation.

PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation

“…These homologies indicate a potential role for PARP-10 as an RNA and/or ssDNA-binding protein. Thus, the lack of inhibition of transformation by the DNES mutants, the potential function in RNA binding, and the recent suggestion for a role of c-Myc in the control of rRNA gene transcription (Poortinga et al, 2004) may hint at a role of PARP-10 together with c-Myc in RNA processing.…”

Nutritional factors and progenitor cell differentiation

“…It has been shown that MEOX2 upregulated by betacarotene in HUVEC, strongly inhibits endothelial cell activation and tube formation in vitro in response to proangiogenic growth factor-VEGF [15]. MAD1L1 up-regulated in HUVEC and in EPC has been proposed as natural antagonist of Myc [16]. MAD can effectively compete with Max and repress transcriptional activity of Myc by binding to the same CACGTG elements of Ebox region [16].…”

“…MAD1L1 up-regulated in HUVEC and in EPC has been proposed as natural antagonist of Myc [16]. MAD can effectively compete with Max and repress transcriptional activity of Myc by binding to the same CACGTG elements of Ebox region [16]. MAD1L1 through effectively competition Myc-Max inhibits Myc activated transcription of molecules participating in proliferation [15,16].…”

“…MAD can effectively compete with Max and repress transcriptional activity of Myc by binding to the same CACGTG elements of Ebox region [16]. MAD1L1 through effectively competition Myc-Max inhibits Myc activated transcription of molecules participating in proliferation [15,16]. EGR-1 Table 1 General overview of pathways regulated by beta-carotene in EPC and HUVEC transcription factor related to differentiation of endothelial cells was up-regulated by BC [17,18].…”

“…Expression of the most regulated genes related to observed biological effects of beta-carotene on HUVEC or EPC e.g. : proliferation (MAD1L1 [16], MEOX2 [15]), differentiation (EGR1 [17,18], MEOX2), apoptosis (BIRC3, BIRC5 [19]), chemotaxis (VCAM 1 [20], IL-8 [21], CCL2 [22]) and homing (CXCR4, CXCL12 [23]) were analysed (Fig. 2).…”