Interferon alpha induces the expression of retinoblastoma gene product in human Burkitt lymphoma Daudi cells: role in growth regulation.

Kumar, Rakesh; Atlas, Ian

doi:10.1073/pnas.89.14.6599

Cited by 74 publications

(40 citation statements)

References 32 publications

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“…This was suggested by a study that looked at involvement of pRb in the growth-regulatory actions of IFN-a by using IFN-a growth-sensitive human Burkitt lymphoma Daudi cells. 39 Treatment of Daudi cells with IFN-a significantly induced pRb protein expression, predominantly as underphosphorylated pRb, by 3-fold to 10-fold, and IFN-a mediated induction of pRb was an early event that preceded the appearance of growth-inhibitory responses and G0/G1 phase arrest of Daudi cells. The mechanism of the observed IFN-a-mediated induction of pRb, however, remains to be delineated.…”

Section: Discussionmentioning

confidence: 99%

Predictive value of p53 and pRb expression in superficial bladder cancer patients treated with BCG and interferon‐alpha

Esuvaranathan

Chiong

Thamboo

et al. 2007

Cancer

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BACKGROUNDNuclear p53 and retinoblastoma protein (pRb) were reported to be poor prognostic indicators for transitional cell carcinoma of the bladder. The authors sought to determine the prognostic value of nuclear p53 and pRb in superficial bladder transitional cell carcinoma patients who were treated with intravesical bacille Calmette‐Guerin (BCG) or BCG with interferon‐alpha (IFN‐α).METHODSA prospective histological review was performed for 80 superficial bladder transitional cell carcinoma patients who underwent postresection intravesical regimes of BCG (81mg, n = 33 or 27 mg, n = 20) or BCG (27 mg) with IFN‐α (n = 27), and followed for a mean of 4.5 years. Hematoxylin and eosin (H & E) and immunoperoxidase staining were performed on tissue sections. Nuclear p53 and pRb immunoreactivity were assessed semiquantitatively, by using a combination of staining extent and intensity, to categorize overexpression or underexpression. Data were analyzed by using chi‐square analysis, multiple logistic regression, and Kaplan‐Meier curves.RESULTSpRb expression was not associated with patient outcome after BCG‐alone therapy, but pRb underexpression was significantly associated with BCG nonresponse and tumor recurrence (P = .047) after BCG and IFN‐α (BCG + IFN‐α) therapy. Low‐grade tumors were associated with pRb overexpression, with or without nuclear p53 underexpression (P = .019; P = .043, respectively). p53 expression alone or in combination with pRb expression had no significant relation with tumor response to BCG alone or BCG + IFN‐α with respect to recurrence, progression, or cancer‐specific death.CONCLUSIONSNuclear pRb underexpression may be predictive of nonresponse and cancer recurrence after intravesical BCG + IFN‐α therapy. Nuclear p53 expression or its combination with pRb expression is not associated with post‐BCG clinical outcome, so p53 expression or p53 with pRb expression should not be used to influence decisions concerning BCG‐alone or BCG + IFN‐α therapy. Cancer 2007. © 2007 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Predictive value of p53 and pRb expression in superficial bladder cancer patients treated with BCG and interferon‐alpha

Esuvaranathan

Chiong

Thamboo

et al. 2007

Cancer

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“…Cell Cycle Analysis-Cell cycle distribution was determined by staining with propidium iodide (Sigma) as described (26). Briefly, cells were stained with propidium iodide and passed through the beam of an argon ion laser turned to 514 (FAC/Scan; Becton Dickinson).…”

Section: Methodsmentioning

confidence: 99%

“…Cell extracts were prepared as described (26). Cell lysate containing equal amounts of total protein (15-25 g) were resolved on a 10% SDSpolyacrylamide gel electrophoresis, followed by probing with an antiBcl-2 mAb (Neomarkers Inc.) using alkaline phosphatase-conjugated second antibody (7,8).…”

Section: Methodsmentioning

confidence: 99%

Bcl-2 Modulates Telomerase Activity

Mandal

Kumar

1997

Journal of Biological Chemistry

143

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Apoptosis is a physiological mechanism of cell death that plays an important role in the regulation of tissue homeostasis. The regulation of apoptosis is a complex process and involves a number of gene products including the survival factor Bcl-2, which has been found to be frequently deregulated in human cancers. In addition to deregulation of apoptosis, the process of neoplasia is also believed to be driven by the activation of telomerase, a ribonucleoprotein complex that adds telomeric repeats (hexanucleotide 5 -TTAGGG-3 ) to the ends of replicating chromosomes. Activation of telomerase has been detected in a vast majority of human cancer cells. Although recent studies have demonstrated the wide occurrence of telomerase activation and Bcl-2 deregulation in human cancer cells, it remains unclear whether there is any linkage between the deregulation of Bcl-2 and telomerase activity in cancer cells. In the studies presented here, we report that the stable overexpression of Bcl-2 in human cancer cells with low Bcl-2 expression was accompanied by increased levels of telomerase activity. In addition, using an IL-2-dependent cytotoxic T-cell line, CTLL-2, we demonstrated that IL-2 deprivation (8 h), which is known to down-regulate Bcl-2 expression, also resulted in concurrent inhibition of telomerase activity in the absence of any detectable apoptosis and accumulation of cells in the G 0 /G 1 phase of the cell cycle. Re-exposure of IL-2-deprived CTLL-2 cells to the recombinant IL-2 led to the up-regulation of both Bcl-2 expression and telomerase activity. Taken together, these findings establish a close linkage between the modulation of telomerase activity by survival factor Bcl-2, and provide a model to study regulation of telomerase activity by an anti-apoptotic pathway that is widely deregulated in cancer cells.

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“…In vivo, they up-regulate expression of tumor-specific antigens, natural killer, and T cell function (7)(8)(9). IFNs also activate growth suppressive proteins such as pRb (10,11), down-regulate c-Myc (12), and suppress activity of transcription factor E2F (13). Protein kinase R and ribonuclease L, which inhibit viral growth in IFN-treated cells (14,15), also play a role in growth suppression (16,17).…”

Section: Ip6k2 Is Post-transcriptionally Induced By Ifn-␤ In Ovarian mentioning

confidence: 99%

Inositol Hexakisphosphate Kinase 2 Mediates Growth Suppressive and Apoptotic Effects of Interferon-β in Ovarian Carcinoma Cells

Morrison

Bauer

Kalvakolanu

et al. 2001

Journal of Biological Chemistry

157

125

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Interferons (IFNs) regulate the expression of genes that mediate their antiviral, antitumor, and immunomodulatory actions. We have previously shown that IFN-␤ suppresses growth of human ovarian carcinoma xenografts in vivo and induces apoptosis of ovarian carcinoma cells in vitro. To investigate mechanisms of IFN-␤-induced apoptosis we employed an antisense technical knockout approach to identify gene products that mediate cell death and have isolated several regulators of interferon-induced death (RIDs). In this investigation, we have characterized one of the RIDs, RID-2. Sequence analysis revealed that RID-2 was identical to human inositol hexakisphosphate kinase 2 (IP6K2). IP6K2 is post-transcriptionally induced by IFN-␤ in ovarian carcinoma cells. A mutant IP6K2 with substitutions in the putative inositol phosphate binding domain abrogates IFN-␤-induced apoptosis. These studies identify a novel function for IP6K2 in cell growth regulation and apoptosis.The interferon (IFN) 1 family of cytokines stimulate antiviral, antitumor, antiproliferative, and immunoregulatory activities (1-3). Upon binding to receptors, IFNs activate a signaling cascade wherein Janus tyrosine kinases induce tyrosine phosphorylation of signal-transducing activators of transcription proteins (4, 5). These transcription factors induce expression of hundreds of genes that possess a wide range of activities (6). Although a great deal is known about antiviral actions of IFNs, mechanisms responsible for their antitumor actions are unclear. In vivo, they up-regulate expression of tumor-specific antigens, natural killer, and T cell function (7-9). IFNs also activate growth suppressive proteins such as pRb (10, 11), down-regulate c-Myc (12), and suppress activity of transcription factor E2F (13). Protein kinase R and ribonuclease L, which inhibit viral growth in IFN-treated cells (14, 15), also play a role in growth suppression (16,17). The family of transcription factors known as IFN gene regulatory factors (IRFs) also mediates the effects of IFNs (18). Two members of this family, IRF-1 and interferon consensus sequence-binding protein (IRF-8) are up-regulated by IFN-␥. Deletion of these genes results in myelodysplasias or chronic myelogenous leukemialike disease (19,20). Because IRFs are transcription factors, and their biological activity depends on genes they induce; characterization of downstream gene products should allow identification of critical regulators of growth suppression.We have previously shown that IFN-␤ suppresses the growth of ovarian tumor xenografts in nude mice (21) and that IFN-␤ induces apoptosis in these cells. To identify death genes we used an antisense technical knockout approach (22). In this approach, death regulatory genes are identified by their ability, when expressed in antisense orientation, to confer resistance to death inducers. Using this technique we have identified several genes, regulators of interferon-induced death (RIDs), that enhance IFN-␤-activated death. In this study we have characterized one of t...

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Interferon alpha induces the expression of retinoblastoma gene product in human Burkitt lymphoma Daudi cells: role in growth regulation.

Cited by 74 publications

References 32 publications

Predictive value of p53 and pRb expression in superficial bladder cancer patients treated with BCG and interferon‐alpha

Predictive value of p53 and pRb expression in superficial bladder cancer patients treated with BCG and interferon‐alpha

Bcl-2 Modulates Telomerase Activity

Inositol Hexakisphosphate Kinase 2 Mediates Growth Suppressive and Apoptotic Effects of Interferon-β in Ovarian Carcinoma Cells

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