Perspectivesin Cancerresearch Induction of Transformed Cells To

[CANCER RESEARCH 47, 659-666, February 1, 1987) Perspectivesin CancerResearch

Induction of Transformed Cells to Terminal Differentiation and the Modulation of Gene Expression1

Paul A. Marks, Michael Sheffery,2 and Richard A. Rifkind

DeWitt Wallace Research Laboratories, Memorial Sloan-Kettering Cancer Center, and the Sloan-Kettering Division of the Graduate School of Medical Sciences, Cornell University, New York, New York 10021

An important problem in biology which has clear relevance strongly inhibited from erythroid cell differentiation and, in for our understanding of neoplastic disease is the mechanism stead, continuously proliferate in the absence of the hormone by which a proliferating population of precursor cells, with the (erythropoietin) normally required for erythroid precursor cell potential for a particular differentiated phenotype, finally with growth and differentiation in vivo. HMBA-mediated commit draws from the cell division cycle and fully expresses the genes ment of MELC to terminal cell division circumvents the block characteristic of the phenotype. Insight into this complex prob ade to differentiation, although the cells do not achieve a lem requires an understanding of basic biological processes completely normal erythroid phenotype (5). Thus, the virus- such as the mechanisms by which cells receive proliferative or induced developmental block does not eliminate the potential differentiation signals from their environment and the ways in of these cells to express their differentiation program. Clearly, which these signals are transduced to alter nuclear events such tumor cells are not necessarily irreversibly blocked in differen as DNA replication and gene expression. Fundamental to our tiation (5,35). Evidence supporting this conclusion derives from understanding of these events is the mechanism by which gene studies of a number of systems. For example, HMBA and expression itself is regulated. A closely related question is the structurally related compounds can induce the expression of nature of the controls involved in the coordinated modulation differentiated characteristics in several different transformed of expression of individual genes (1-3). cells in vitro (37). A variety of agents can also induce both No single cell system has been identified which appears ideal transformed cell lines and several human primary tumor ex- for analysis of the regulation of cell proliferation, gene expres plants to express differentiated characteristics (10-35). Studies sion, and the nature of coordinated changes in gene activity with temperature-sensitive transforming viruses (38, 39) which during differentiation. Nevertheless, the MELC3 (4), a rapidly block normal development at permissive temperatures but per proliferating, virus-transformed erythroid precursor which can mit expression of the differentiated phenotype at nonpermissive be induced to cease cell proliferation and express many func temperatures also support the conclusion that cellular transfor tions of erythroid differentiation, does provide a suitable model mation need not destroy differentiation potential. In further for characterizing alterations in gene expression during termi support are studies with the malignant mouse teratocarcinoma nal differentiation (5-8). MELCs are unipotential in terms of cells which, upon implantation into the inductive environment their differentiated phenotype. They are not a model for study of the early mouse embryo, can differentiate and participate in ing factors regulating multilineage cell differentiation, such as the formation of all normal tissues of the chimeric mouse (40). the hematopoietic stem cell, let alone analysis of early embry onic cell differentiation (9). Clearly, understanding the regula Characteristics of HMBA-mediated MELC Differentiation tion of the coordinated expression of specific genes which occurs during terminal differentiation is a challenge which is It is well to consider the cellular aspects of HMBA-induced being examined in several normal and transformed cell lineages MELC terminal differentiation to provide a context for a review (10-35). This review will focus on the specific case of HMBA- of the modulation in gene expression during this process. induced MELC differentiation to the terminal erythroid phe MELCs are transformed erythroid precursors. The trans notype (36). We consider in detail the changes in expression of formed cell appears to be blocked in development approxi genes related to the differentiated phenotype, namely, ai- and mately at the stage of the colony-forming cell (CFUe) (5, 7). /8maj-globins;a gene related to the general metabolic function of Despite repeated cloning they retain their normal develop the cell, namely the rRNA gene; and the protooncogenes c- mental potential, as demonstrated by the ease with which they myb, c-myc, and c-fos and the p53 gene. The products of these can be induced to differentiate. MELCs have a number of latter genes are nuclear proteins which have been implicated in characteristics which make them particularly useful for exam regulating cell proliferation and differentiation. ining the coordinated modulation of gene expression observed during terminal differentiation. They can be maintained for an essentially unlimited period of time, under in vitro conditions, Transformation Need Not Destroy Differentiation Potential as a relatively homogeneous population (4). Variants blocked at different steps in the inducer-mediated developmental path Viral transformation of MELC alters the normal mechanisms of the cell for regulating cell proliferation and erythroid differ way have been isolated and are likewise stably maintained in entiation. As a consequence, the virus-transformed cells are culture (41, 42). Upon culture with HMBA or other agents, MELCs are induced to express a developmental program sim Received 8/22/86; accepted 10/16/86. 1These studies were supported, in part, by grants from the NIH (CA-31768, ilar to that observed during normal terminal erythroid differ CA-08748 and AM-37513), the Bristol-Myers Cancer Research Award, and the entiation. Life and Health Insurance Medical Research Fund. The kinetics of commitment of MELC to terminal cell divi 2Recipient of a Miriam and Benedict Wolf Fellowship. 'The abbreviations used are: MELC, murine erythroleukemia cell; HBBA, sion is consistent with a stochastic or probablistic process (43, hexamethylene bisacetamide; pS3, M, 53,000 protein; CFUe, colony-forming 44). Detectable commitment of MELC in culture with HMBA units-erythroid. occurs as early as 12 h and progressively increases so that 659 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1987 American Association for Cancer Research. TRANSFORMED CELL DIFFERENTIATION AND GENE EXPRESSION almost the entire population is committed by 48 to 60 h of methyl sulfoxide- or HMBA-induced differentiation in MELC exposure to the inducer. (63). Taken together, these findings suggest that an effect on HMBA-mediated MELC terminal cell differentiation is a the regulation of protein kinase C activity by diacylglycerol may multistep process (8, 45) (Fig. 1). HMBA initiates a number of play a role in HMBA-mediated induction of terminal differen early metabolic changes (within 8-10 h) which precede irrevers tiation. ible commitment to differentiation (45-47). Among these early Studies with inhibitors of HMBA-induced terminal differ changes are alterations in membrane ion permeability (48, 49), entiation have provided additional evidence with respect to the alterations in membrane fluidity (50,51), changes in cell volume multistep process involved in inducer-mediated differentiation and a transient increase in cyclic AMP concentration (52, 53), (43, 63-65). Dexamethasone suppresses the expression of as well as changes in the expression of certain protooncogenes HMBA-mediated MELC terminal cell division and the accu c-myb, c-myc, and c-fos and the p53 gene (47, 54-56). During mulation of globin mRNAs (45, 66). The glucocorticoid blocks this early or "latent" period, there is no detectable commitment a late step in the process, a step which is not rate limiting. to terminal cell division as assayed by the incapacity of the cells Dexamethasone does not appear to inhibit the inducer-media to express terminal differentiation upon removal of the inducer. ted early changes during the precommitment latent phase, With more prolonged culture with HMBA, MELC become characterized by a variety of metabolic changes already de irreversibly committed to differentiate and can be removed from scribed. This dexamethasone-insensitive precommitment stage culture with HMBA and still go on to express the differentiated is followed by a period during which there accumulate one or phenotype including hemoglobin accumulation and cessation more factors required for commitment to terminal cell division of cell division (43, 44). Morphological and biochemical and for expression of the genes (such as the globins) character changes occur which are similar to normal erythroid terminal istic of the terminal erythroid phenotype (45, 66). cell differentiation and which involve the coordinated expres Commitment of MELC to irreversible terminal cell differ sion of a number of genes, including a- and 0-globin, heme- entiation appears to require progression of the cell through at synthetic enzymes, erythroid-specific membrane proteins, as least one S phase of the cell division cycle in the presence of well as the suppression of DNA replication, and suppression of the inducer (67-70). The significance of this requirement for rRNA synthesis (5, 7). There is evidence that the coordinated DNA replication in the presence of inducer is not known. It is expression of these inducer-mediated changes in gene expres possible that there is an even more discrete period during sion does not involve an obligatory, sequential series of steps. replication of the MELC genome which is critical for HMBA- For example, with certain variant cell lines, such as 745A- mediated initiation of developmental progression. DR10, HMBA can induce accumulation of a- and /3-globin without initiating commitment to terminal cell division (42). Further, hemin can induce MELC to accumulate a- and ÃŸ- Modulation of Gene Expression globin mRNA without commitment to terminal cell division The expression of a number of genes is altered during MELC (57-59). differentiation. We focus in this review on the aÂ¡-and ÃŸm*i- The mechanism of action of HMBA is not known. There is globin genes; rRNA genes; c-myc, c-myb, and c-fos protoonco evidence that polar-planar compounds, such as dimethyl sulf- genes; and the p53 gene. Modulation of expression of genes oxide, cause a significant decrease in the levels of phosphatidyl- during HMBA-induced MELC differentiation can occur by one inositol metabolites, including inositol triphosphate and diac- of several mechanisms. These include: (a) modification of the ylglycerol within 2 h of onset of culture (60). Diacylglycerol primary base structure of DNA, for example, base modification activates the ( ';r ' - and phospholipid-dependent protein kinase by methylation or demethylation of cytosine (71); (h) changes C activity (61) and is associated with pro 1iterative responses to in the rate of transcriptional activity, modified by m-acting a range of mitogens (60). Diacylglycerols have also been re DNA sequences such as promoters and enhancers, and their ported to inhibit dimethyl sulfoxide-induced differentiation interactions with transacting proteins (72-79); (<â€¢)alterationin (62). The tumor promoter 12-0-tetradecanoylphorbol-13-ace- the processing, transport, or stability of mRNA; and (d) trans- tate, which also activates protein kinase C, can suppress di- lational and posttranslational modification of the gene product.

MEMBRANE MODULATION OF TERMINAL DIVISIONS Fig. 1. Working model for the effects of CHANGES GENE EXPRESSION SYNTHESIS HMBA on MELCs. Horizontal arrows, pro posed sequence of events initiated by HMBA Prolonged GÃ¬ leading to terminal differentiation of the trans formed MELC. The arrows do not imply es (l) [Diacylglycerol] c-myc: (I) e-myc: (+) tablished cause and effect relationships. Mod ulation in gene expression is indicated as fol (4) Protein Kinne C c-niyn: (i) c-myb: (I) lows: +, gene is actively transcribed in unin- (t) CiÂ»' tnntport c-Fos: (t) c-Fos: (t) duced MELCs or transcribed at a level com PÂ»:Â« P53:<*) parable to that in uninduced cells; -, gene not transcribed or transcribed at a very low level; rRNA: (+) rRNA: (-) \, HMBA leads to an increase in the expression Nucleosome pattern of this gene; J. decrease in gene expression. Nucleosome disrupted ,/ and p*" globins: (-) a'< /3-*gloWns (tt) Details are discussed in the text. During the early latent period, when MELCs are still un t 2-3x DNase sensitivity DNase HSS committed, there is modulation of expression Hypomethylated Nucleosomes disrupted of c-myb, c-myc, c-fos, and p53, as indicated, Nucleosomes partial disruption Hypomethylatlon unchanged but no change in expression of the rRNA, MI Heme synthetic enzymes (t) or /S^-globin genes compared with uninduced etc. cells. DNase HSS, DNase I hypersensitive site.

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Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1987 American Association for Cancer Research. TRANSFORMED CELL DIFFERENTIATION AND GENE EXPRESSION comparison to the ÃŸa"i/ÃŸmi'1globingene domain, the nontran- Globin Genes scribed embryonic and ^-homologous gene domain is relatively The activation of transcription of the a,- and jS insensitive to DNase I or micrococcal nuclease digestion (79, genes is distinctly not, as already noted, the earliest effect of 94, 95). HMBA, but it is the most extensively studied and, quantita HMBA causes no evident change in the pattern of methyla tively, the most striking. During HMBA-induced MELC dif tion of DNA in the globin gene domains (84). The inducer ferentiation there is a 10- to 30-fold increase in the level of does, however, cause certain changes in chromatin structure globin mRNA due, primarily, to an increase in globin gene which include disappearance of the second intron DNase I- transcription (76, 77). hypersensitive site of the ^"""-globin gene, appearance of DNase In MELC, two /3-like globin genes are expressed, ÃŸm''and I-hypersensitive sites within 100 base pairs 5' of both the <Â», /3min,probably two a-globin genes, ai and a2 (78, 79). In unin- and /3miUgenes (82-86) and appearance of another DNase I- duced MELC there is a low constitutive level of expression of hypersensitive site about 3000 base pairs upstream of the cap both the a,- and /3mrn-globingenes (80-81). HMBA initiates site of the /S^-globin (96). HMBA initiates further nucleosome marked activation of transcription of the at and ÃŸ""*genes.The disruption limited to the transcribed regions of the ar and /3n"li- increased rate of transcription of the <*,-globin gene is detectable globin gene domain (85). This increase in nucleosome disrup within 12 to 24 h of exposure to HMBA and achieves a 20- to tion is most pronounced at the 5' end and decreases toward the 30-fold increase in rate of transcription by approximately 36 h 3' end of each of the transcribed globin genes. Time course (82). By comparison, activation of/3mi

(124), and HMBA- or dimethyl sulfoxide-induced MELC (47, commitment to terminal cell division and onset of transcription 55). c-myb is the natural homologue of the transforming gene of the a-globin gene (8, 66). of avian myeloblastosis virus which causes myeloblastic leuke More recently we have determined that dexamethasone, while mia in chickens (125). The c-myb gene is abundantly expressed not inhibiting the HMBA-induced early decrease in c-myb and in human and mouse hemopoietic tumors (126-128). c-myc mRNA or the increase in c-fos mRNA, does prevent the Accumulation ofc-fos mRNA is associated with both normal persistent suppression of c-myb mRNA characteristic of indu and induced differentiation (114, 115, 118, 129, 130). Trans- cer-mediated commitment to irreversible terminal cell differ lection of the C-/0S gene into F9 teratocarcinoma cells results entiation (47). Hemin, which induces MELCs to accumulate in expression of the c-fos gene and accumulation ofc-fos mRNA globin mRNA but does not induce commitment to terminal cell and protein. These transfected F9 cells lose their capacity to division (57-59), has no effect, early or late, on c-myc, c-myb, proliferate and commence expression of their differentiated or c-fos mRNA levels. Taken together, the early modulations characteristics (114). of protooncogene expression observed when MELCs are treated The p53 gene product is a nuclear protein which may be with HMBA may be important events in initiating differentia important in determining normal cell cycle progression from tion, while persistent suppression of c-myh may be a critical G, to S (131). It has also been suggested that p53 protein levels factor in permitting the cells to proceed to commitment to may be regulated in relation to the differentiation status of a terminal cell division and expression of genes related to the cell lineage. differentiated phenotype (47). Analysis of the changes in expression of the protooncogenes c-myb, c-myc, and c-fos and the p53 gene during induced MELC Summary terminal differentiation reveals a complex pattern of changes in expression (47, 54-56). During the early latent precommit- HMBA induces MELCs to terminal erythroid differentiation. ment period there is a pronounced decrease in c-myb and c-myc The mechanism of HMBA action is not known. During induc mRNA and an increase in c-fos mRNA (within 1 to 4 h). No tion there are early changes in cell function and gene expression increase is detected in the level of p53 mRNA, although the during the latent period prior to commitment to terminal level of p53 protein (detected by monoclonal antibodies 200-47 differentiation, changes which appear to accompany commit and I'Ah 421) decreases during this early period (132). ment, and changes which characterize the expression of differ Culture of MELC with HMBA beyond 10 to 12 h leads to entiation in the committed cell. The inducer causes an early (within 2 h) decrease in diacylglycerol concentration and a irreversible commitment as already defined, and over 95% of decrease in Ca2+ and phospholipid-dependent protein kinase C the cells are committed by 48 h (47). Commitment to terminal cell division is accompanied by persistent suppression of c-myb activity. Early suppression (within 1-2 h) of c-myb and c-myc mRNA and an increase in c-fos mRNA, whereas the initial low gene transcription and an increase in c-fos mRNA (within 4 h) level of c-myc mRNA is transient; c-myc mRNA increases, may reflect alterations in protein kinase C-mediated signals required for expression of these protooncogenes. HMBA-in returning to levels found in uninduced cells by 10 to 12 h. The mechanism of HMBA-induced suppression of c-myb and duced commitment to terminal differentiation is detected by 12 c-myc mRNA levels involves an inhibition of transcription h and over 95% are committed cells by 48 to 60 h. Commitment is associated with persistent suppression of c-myb gene tran within 15 to 60 min (47). Cycloheximide does not prevent this scription and elevated levels of c-fos mRNA whereas c-myc HMBA-mediated suppression of protooncogene transcription, mRNA returns to control levels. Transcription of the erythroid- suggesting that their transcription is not dependent on protein specific genes, at- and ÃŸm*i-g\obin,isincreased 10- to 30-fold synthesis. The HMBA-induced increase in c-fos mRNA, how while synthesis of rRNA is suppressed and there is activation ever, does apparently involve posttranscriptional mechanisms which are sensitive to modulation by a short-lived protein the or suppression of a number of additional genes which remain to be characterized. suppression of which by cycloheximide leads to a marked It is not yet clear how the protein products of protooncogenes increase in c-fos mRNA levels in MELC both in the presence elicit or modify cellular responses. Changes in expression of c- and absence of HMBA (47). myb, c-myc, c-fos, and p53 genes which occur during HMBA- Evidence has accumulated that c-myb (128), c-myc (122), as induced differentiation, as well as in several other systems, do well as C-./W.V(133)mRNA levels may be principally regulated suggest that products of these genes control multiple functions at a posttranscriptional level in proliferating cells. Thus, the and, by implication, affect expression of multiple genes. Some mechanisms regulating expression of c-myb and c-myc during clues exist, e.g., the observation that cells transfected with c- HMBA-induced terminal differentiation may differ from those myc have an increased ability to promote the expression of regulating their expression in continuously proliferating cells. certain endogenous genes. The evidence that increased expres Transfection of MELC with c-myc leads to constitutive sion of c-myc and c-myb is associated with the proliferative expression of that gene and a block in dimethyl sulfoxide- state and that induced suppression of these genes is associated induced differentiation (122). Transient suppression of protein with commitment to terminal cell division, while increased synthesis by exposure of dimethyl sulfoxide-treated c-myc- expression of c-fos is associated with differentiation, suggests transfected cells to cycloheximide for 30 min is sufficient to that the protein products of these genes can affect genes with initiate commitment to terminal cell differentiation. These re products that, in turn, are critical for cell proliferation or sults have been interpreted to mean that inducer-mediated progression toward the terminal differentiated phenotype. The changes on the path to commitment can occur in the presence possible cause and effect relationships between changes in pro of constitutively high levels of c-myc mRNA but expression of tooncogene expression and terminal differentiation are yet to the terminal erythroid phenotype is blocked. In this context it be established but HMBA-mediated differentiation of MELC is useful to recall that the corticosteroid, dexamethasone, will remains an attractive model for pursuing these questions. block HMBA-mediated terminal erythroid differentiation but One possible application of the established pattern of upon removal of the steroid there is prompt expression of HMBA-induced modulation of gene expression during MELC 663

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Paul A. Marks, Michael Sheffery and Richard A. Rifkind

Cancer Res 1987;47:659-666.

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