Recessive genetic deregulation abrogates c-myc suppression by interferon and is implicated in oncogenesis.

Abstract

In a previous study we demonstrated that many hematopoietic tumor cells are resistant to the inhibitory effects that interferon exerts on c-myc mRNA expression without losing other receptor-mediated intracellular responses (M. Einat, D. Resnitzky, and A. Kimchi, Nature [London] 313:597400). We report here that this partial resistance was overridden in two independent stable somatic cell hybrids prepared by fusion between sensitive and resistant cells. The c-myc mRNA transcribed from the active allele of the resistant parent cell was reduced by interferon within the context of the cell hybrid. It was therefore concluded that changes in the cis-acting sequences of c-myc were not involved in this type of relaxed regulation and that resistance resulted rather from inactivation or loss of postreceptor elements which operate in trans. The growth-stimulating effect that this genetic deregulation might have on cells was tested in experimental systems of cell differentiation in which an autocrine interferon is produced. For that purpose we isolated variant clones of Ml myeloid cells which were partially resistant to alpha and beta interferons and tested their growth behavior during in vitro-induced differentiation. The resistant clones displayed higher proliferative activity on days 2 and 3 of differentiation than did the sensitive clones, which stopped proliferating. The loss of c-myc responses to the self-produced interferon disrupted the normal cessation of growth during differentiation and therefore might lead cells along the pathway of neoplasia.

Molecular mechanisms underlying interferon-α-induced G0/G1 arrest: CKI-mediated regulation of G1 Cdk-complexes and activation of pocket proteins

“…Another well-established e ect is their antiproliferative action, and IFNs are known to e ectively inhibit growth of various untransformed and transformed cells (Taylor and Rozengurt, 1985). This e ect of IFNs has also been postulated to mediate, at least in part, their antitumor e ects observed in some malignancies (Brenning et al, 1985;Kimchi et al, 1988). A number of proteins previously identi®ed as key regulators of the cell cycle, such as c-myc, pRb, cyclic A, Cdk2, E2F, have been demonstrated as downstream targets in the growth-suppressive activity of IFNs (Kimchi, 1992;Grande r et al, 1997).…”

Cell cycle regulation of the double stranded RNA activated protein kinase, PKR

“…Type 1 interferons are known to mediate inhibition of c-myc expression (Einat et al, 1985;Kimchi et al, 1988), inhibition of RB phosphorylation (Thomas et al, 1991;Resnitzky et al, 1992;Kumar and Atlas, 1992;Burke et al, 1992), reduction of cyclin a Cell cycle regulation of PKR M Zamanian-Daryoush et al A levels (Thomas et al, 1991;Resnitzky et al, 1992;Kumar and Atlas, 1992;Burke et al, 1992;Bybee and Thomas, 1992), suppression of E2F DNA binding activity (Melamed et al, 1993;Iwase et al, 1997), induction of the cdk inhibitor p21 (Subramanian and Johnson, 1997), and suppression of cyclin D3 and cdc25A genes (Tiefenbrun et al, 1996). The ectopic expression of two catalytically inactive mutants of PKR in mouse M1 myeloid leukemia cells interfered with IFN-induced suppression of c-myc protein without aecting IFN-induced RB de-phosphorylation or cyclin D/A protein levels (Raveh et al, 1996).…”

Interferons and interleukin-6 suppress the DNA-binding activity of E2F in growth-sensitive hematopoietic cells.

“…This approach has been applied in recent years to the study of the growth-suppressive effects of a few cytokines, including interferons (IFNs) and interleukin-6 (IL-6) (reviewed in reference 30). Cell lines that arrest in response to the cytokine in the GJG1 phase of the cell cycle, such as human Daudi Burkitt lymphoma and murine Ml myeloblastic cells (14,31,48,49,54), were specifically chosen for these studies. The first genes that were identified as downstream targets along the IFN-and IL-6-triggered molecular pathways were c-myc and the cyclin A and retinoblastoma (RB) genes (14,31,48,49).…”

“…Cell lines that arrest in response to the cytokine in the GJG1 phase of the cell cycle, such as human Daudi Burkitt lymphoma and murine Ml myeloblastic cells (14,31,48,49,54), were specifically chosen for these studies. The first genes that were identified as downstream targets along the IFN-and IL-6-triggered molecular pathways were c-myc and the cyclin A and retinoblastoma (RB) genes (14,31,48,49). While c-Myc and cyclin A responded by reduction in the mRNA and protein expression, RB gene product (pRB) responses occurred at the posttranslational level and consisted of conversion of the protein into the underphosphorylated functional forms (49).…”