In K562 leukemia cells treated with doxorubicin and hemin, a decrease in c-myc mRNA expression correlates with loss of self-renewal capability but not with erythroid differentiation

Toffoli, Giuseppe; Viel, Alessandra; Bevilacqua, C.; Maestro, Roberta; Tumiotto, Loretta; Boiocchi, Mauro

doi:10.1016/0145-2126(89)90064-7

Cited by 14 publications

(7 citation statements)

References 9 publications

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“…26 Moreover, differentiation of K562 cells by erythroid inducers is associated with an increase of haemoglobin synthesis but not always with an irreversible cell terminal division. 27 Our studies show that the upregulation of Bcl-X L during DMSO induction of F-MEL cells is not correlated with haemoglobinization but rather with their accumulation in the G0/G1 phase of the cycle. It is possible that Bcl-X L induction in DMSO-treated F-MEL cells facilitates erythroid differentiation not only by delaying apoptosis but also by inducing cell cycle arrest or by inhibiting re-entry of differentiating cells into the cell cycle as recently described for Bcl-2.…”

Section: Discussionmentioning

confidence: 49%

Bcl-XL induction during terminal differentiation of Friend erythroleukaemia cells correlates with delay of apoptosis and loss of proliferative capacity but not with haemoglobinization

et al. 1999

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Friend murine erythroleukaemia (F-MEL) cells are a useful model for studying the processes that regulate erythroid differentiation since exposure of these cells to chemical inducers (DMSO or HMBA) results in commitment to terminal cell division and synthesis of haemoglobin. This study examined the relationship between differentiation and apoptosis in DMSO sensitive and resistant F-MEL cells. Clear apoptosis was not observed in DMSO-treated sensitive F-MEL (strain 745A) cells during the induction of differentiation. In contrast, DMSO-induced 745A cells exhibited delayed apoptosis compared to uninduced cells. Since the Bcl-2 family members play a major role in the control of apoptosis and/or differentiation, we determined their expression before and after DMSO or HMBA treatment. Neither untreated nor chemically-induced 745A cells expressed the Bcl-2 protein. The levels of Bax and Bad proteins remained relatively constant during DMSO-induced differentiation. DMSO or HMBA treatment of 745A cells induced a marked increase of Bcl-XL expression during the late phase of differentiation which persisted even when the cells began to die. This upregulation of Bcl-XL was independent of cell density but was correlated with cell arrest in G0/G1. DMSO treatment induced a similar delay of apoptosis and enhancement of Bcl-XL expression in F-MEL (strain TFP10) cells which fail to synthesize haemoglobin in the presence of DMSO. Dexamethasone, which blocks DMSO-induced differentiation of F-MEL cells, prevented the induction of Bcl-XL. Inhibitors such as imidazole or succinylacetone, which inhibit haemoglobin synthesis but not commitment to terminal cell division, did not suppress Bcl-XL induction in DMSO-induced cells. Taken together, these results indicate that DMSO treatment of F-MEL cells induces a marked increase in Bcl-XL expression suggesting a role for this anti-apoptotic protein in the process of erythroid differentiation in F-MEL cells. Moreover, induction of Bcl-XL during this process seems to be associated with loss of proliferative capacity rather than with haemoglobin synthesis.

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Section: Discussionmentioning

confidence: 49%

Bcl-XL induction during terminal differentiation of Friend erythroleukaemia cells correlates with delay of apoptosis and loss of proliferative capacity but not with haemoglobinization

et al. 1999

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“…Doxorubicin, TMPyP4, and GQC-Qi have all been noted to decrease MYC expression (39,48) and were tested for exon-specific effects as a measure of potential activity on the G4; however, no compound mirrored the effect of GQC-05. Previous studies, both from our research group and others, have focused on the pair of BL cell lines (either RAMOS or RAJI and CA46) to describe potentially focused action of small molecules (39,43,48). However, the newly described CA46 test is much more robust and direct in demonstrating MYC G4-targeted activity, acting as its own isogenic control.…”

Section: Discussionmentioning

confidence: 99%

Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

Brown

Danford

Gokhale

et al. 2011

Journal of Biological Chemistry

157

221

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Most transcription of the MYC proto-oncogene initiates in the near upstream promoter, within which lies the nuclease hypersensitive element (NHE) III 1 region containing the CT-element. This dynamic stretch of DNA can form at least three different topologies: single-stranded DNA, double-stranded DNA, or higher order secondary structures that silence transcription. In the current report, we identify the ellipticine analog GQC-05 (NSC338258) as a high affinity, potent, and selective stabilizer of the MYC G-quadruplex (G4). In cells, GQC-05 induced cytotoxicity with corresponding decreased MYC mRNA and altered protein binding to the NHE III 1 region, in agreement with a G4 stabilizing compound. We further describe a unique feature of the Burkitt's lymphoma cell line CA46 that allowed us to clearly demonstrate the mechanism and location of action of GQC-05 within this region of DNA and through the G4. Most importantly, these data present, as far as we are aware, the most direct evidence of intracellular G4-mediated control of a particular promoter.The MYC proto-oncogene is a key component of normal cell growth and differentiation, with roles in a multitude of cellular processes. Normally, this gene is subject to tight transcriptional regulation; however, aberrant MYC expression is a common feature in an estimated 80% of all human malignancies (1-3); it is estimated that one-seventh of cancer deaths in the United States are associated with alterations in the MYC gene or its expression (4). Deregulation can arise through a variety of mechanisms (5-13), but most often MYC is activated through alterations in cell signaling that lead to increased transcription (14).Deregulated MYC can lead to transformation (15), often as an early step in the process of multistage cancer development, and one on which all other mutations are based (16,17). Cancer cells appear to be addicted to a deregulated MYC (18), which can be the "Achilles heel", offering the potential for a therapeutic window (19,20). The ability to selectively and potently down-regulate MYC would have considerable potential for both efficacy and safety in a variety of tumor types.There are several upstream elements within the MYC promoter that can potentially undergo strand separation to form either single-stranded or other non-B-DNA structures (21), which play a critical role in transcriptional control of MYC: the distant Far Upstream Element acts as a cruise control element, Z-DNA found both in the far upstream and the promoter regions, and a GC-rich region within the proximal promoter that acts as an on/off switch (22-28). This near upstream core promoter region, which is responsible for the initiation of 80 -90% of MYC transcription (29), contains the GC-rich nuclease hypersensitive element (NHE) 2 III 1 to which doublestranded (Sp1) and single-stranded (CNBP and hnRNP k) transcriptional factors bind. Within the MYC gene's NHE III 1 , a 31-base pair element consisting of five repeats of the sequence (C/T)C(C/T)TCCCCA serves as the "on/off switch" for MYC trans...

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“…Filters were prehybridised, hybridised and washed as de-scribed (Toffoli et al, 1989b) (Merkel et al, 1989), a human P-actin fragment (0.7 kb) derived from BamHI-EcoRI digested plasmid pHFPA-3'UT (Ponte et al, 1983 Cells size was determined using 3H20 and D-1-'4C mannitol as described (Long & Stringfellow, 1988 …”

Section: Cell Linesmentioning

confidence: 99%

Pleiotropic-resistant phenotype is a multifactorial phenomenon in human colon carcinoma cell lines

Toffoli

Viel²,

Tumiotto³

et al. 1991

Br J Cancer

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In K562 leukemia cells treated with doxorubicin and hemin, a decrease in c-myc mRNA expression correlates with loss of self-renewal capability but not with erythroid differentiation

Cited by 14 publications

References 9 publications

Bcl-XL induction during terminal differentiation of Friend erythroleukaemia cells correlates with delay of apoptosis and loss of proliferative capacity but not with haemoglobinization

Bcl-XL induction during terminal differentiation of Friend erythroleukaemia cells correlates with delay of apoptosis and loss of proliferative capacity but not with haemoglobinization

Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

Pleiotropic-resistant phenotype is a multifactorial phenomenon in human colon carcinoma cell lines

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