Cancer and the cell cycle

Ford, Heide L.; Pardee, Arthur B.

doi:10.1002/(sici)1097-4644(1999)75:32+<166::aid-jcb20>3.0.co;2-j

Cited by 69 publications

(37 citation statements)

References 49 publications

(45 reference statements)

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“…Alterations in cell cycle proteins and their regulation are clearly involved in cancer progression and cellular transformation pathways (22), and HBx-induced changes in normal proliferation pathways in hepatocytes, especially its induction of cell cycle entry of normally quiescent hepatocytes, may facilitate HBV replication while ultimately proving detrimental to normal hepatocyte physiology. Consequently, understanding the molecular mechanisms that are associated with HBx-induced cell cycle progression and its effect on normal hepatocyte physiology may also help elucidate mechanisms that link chronic HBV infections to the development of liver cancer.…”

Section: Vol 84 2010mentioning

confidence: 99%

The Hepatitis B Virus X Protein Modulates Hepatocyte Proliferation Pathways To Stimulate Viral Replication

Gearhart¹,

Bouchard

2010

J Virol

101

121

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Worldwide, there are over 350 million people who are chronically infected with the human hepatitis B virus (HBV); chronic HBV infections are associated with the development of hepatocellular carcinoma (HCC). The results of various studies suggest that the HBV X protein (HBx) has a role in the development of HBVassociated HCC. HBx can regulate numerous cellular signal transduction pathways, including those that modulate cell proliferation. Many previous studies that analyzed the impact of HBx on cell proliferation pathways were conducted using established or immortalized cell lines, and when HBx was expressed in the absence of HBV replication, and the precise effect of HBx on these pathways has often differed depending on experimental conditions. We have studied the effect of HBx on cell proliferation in cultured primary rat hepatocytes, a biologically relevant system. We demonstrate that HBx, both by itself and in the context of HBV replication, affected the levels and activities of various cell cycle-regulatory proteins to induce normally quiescent hepatocytes to enter the G 1 phase of the cell cycle but not to proceed to S phase. We linked HBx regulation of cell proliferation to cytosolic calcium signaling and HBx stimulation of HBV replication. Cumulatively, our studies suggest that HBx induces normally quiescent hepatocytes to enter the G 1 phase of the cell cycle and that this calcium-dependent HBx activity is required for HBV replication. These studies identify an essential function of HBx during HBV replication and a mechanism that may connect HBV infections to the development of HCC.Viruses often encode proteins that modulate normal cellular processes to create an environment that facilitates viral replication. A potential consequence of the activities of viral proteins that alter normal cellular signaling pathways is that they can stimulate cell transformation and cancer progression. Included among confirmed oncogenic viruses is the hepatitis B virus (HBV); HBV is the prototype member of the Hepadnaviridae, a family of hepatotropic viruses (57). The HBV genome is a partially double-stranded, circular DNA that contains four overlapping open reading frames (ORFs) that encode the viral envelope, capsid, reverse transcriptase, and X (HBx) proteins (57). Worldwide, there are over 350 million people who are chronically infected with HBV; approximately 25% of these chronically HBV-infected individuals develop hepatocellular carcinoma (HCC) (3, 57). While there is evidence of a strong link between chronic HBV infections and HCC development, exactly how chronic HBV infections can lead to the development of HCC has not been defined. The results of numerous studies suggest that the development of HBV-associated HCC involves a combination of the activities of HBV proteins that modulate cell signal transduction pathways, such as HBx, and the consequences of the host immune response to infection, including immune-mediated destruction of HBV-infected hepatocytes that induces repeated liver regeneration cycles.HBx is a...

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Section: Vol 84 2010mentioning

confidence: 99%

The Hepatitis B Virus X Protein Modulates Hepatocyte Proliferation Pathways To Stimulate Viral Replication

Gearhart¹,

Bouchard

2010

J Virol

101

121

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“…Cyclin A/cdk2 governs S-phase progression and the production of proteins involved in dna synthesis 9,10 . Cyclin A/cdk2 also inactivates E2F [11][12][13][14] .…”

Section: This Scientific Paper Is the Work Of The Author And Was Madementioning

confidence: 99%

“…Mitosis is regulated by the anaphase-promoting complex/cyclosome and by degradation of cyclin B 10 . The assembly of a bipolar spindle by the centrosome is monitored by a checkpoint that senses microtubule defects or aberrant kinetochore attachment [19][20][21] .…”

Section: This Scientific Paper Is the Work Of The Author And Was Madementioning

confidence: 99%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

193

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Modulation of the cell cycle also contributes to chemotherapy resistance. The cyclin-dependent kinases (cdks), the essential engines of the cell cycle, are therefore rational therapeutic targets. Over the last several years, a new class of anticancer therapy has been developed and extensively tested: inhibitors of cdks.These drugs have been tested as single agents with modest results. However, in combination with traditional cytotoxic chemotherapy, they have the potential to overcome drug resistance and to improve cytotoxic efficacy. THE CELL CYCLE AND ITS REGULATIONThe cell cycle governs the transition from quiescence (G0) to proliferation while ensuring the fidelity of the genetic transcript. The phases associated with dna synthesis (S phase) and mitosis (M phase) are separated by the gaps G1 and G2. The cdks join with regulatory proteins called cyclins to drive the cell through the cycle.Inhibitory proteins [cdk inhibitors (cdkis)] block specific interactions. The Ink4 (inhibitor of cdk4) class of cdkis (p16 Ink4a , p15 Ink4b , p18 Ink4c , and p19 Ink4 ) bind and inhibit cyclin D-associated kinases (cdk2, -4, and -6), and the kinase inhibitor protein (Kip) group of cdkis (p21 Waf1 , p27 Kip1 , and p57 Kip2 ) block the cyclin E/cdk2 and cyclin A/cdk2 complexes 1 .The pattern of cyclin expression defines the cell's progression through the cycle 2,3 . At least 9 cdks (cdk1-cdk9) and many cyclins (cyclin A-cyclin T) are known. The cdk /cyclin complexes are activated by specific phosphorylation of the cdk by cdk7/cyclin H, also called cdk-activating kinase 4 . Specific complexes regulate each step of the cycle. Cyclins D1-D3/cdk2, -4, and -6 drive progression through G1; cyclin E/cdk2 controls entry into S phase; cyclin A/cdk2 controls S-phase progression; cyclin A/ cdk1 (also known as cdc2) controls G2; and cdk1/ cyclin B facilitates mitosis.Entry into the cell cycle (G1) is governed by the restriction point, beyond which progression through the cycle is independent of stimuli such as ABSTRACTThe cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases (cdks) and the regulatory proteins called cyclins. The cdks are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of cdks can also block transcription.Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit ma...

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“…2-4). A block in differentiation is often linked to deregulation of cell proliferation as evident by the altered cell cycle in cancer cells (31). We therefore measured the growth rates of 32D stable cell lines expressing the wild-type and mutant proteins.…”

Section: Impaired Subnuclear Targeting Of Aml1 Alters Myeloid Progenitormentioning

confidence: 99%

Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype

Vradii

Zaidi

Lian

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The multifunctional C terminus of the hematopoietic AML1 transcription factor interacts with coregulatory proteins, supports the convergence and integration of physiological signals, and contains the nuclear matrix targeting signal, the protein motif that is necessary and sufficient to target AML1 to subnuclear sites. The (8;21) chromosomal translocation, which replaces the C terminus of AML1 with the ETO protein, modifies subnuclear targeting of AML1 in acute myeloid leukemia (AML) and results in defective myelopoiesis. We therefore addressed the relevance of AML1 subnuclear targeting and associated functions that reside in the C terminus to myeloid differentiation. A single amino acid substitution that abrogates intranuclear localization was introduced in the AML1 subnuclear targeting signal. Expression of the mutant AML1 protein blocks differentiation of myeloid progenitors to granulocytes in the presence of endogenous AML1 protein, as also occurs in the (8;21) chromosomal translocation, where only one allele of the AML1 gene is affected. The cells expressing the mutant AML1 protein continue to proliferate, maintain an immature blast-like morphology, and exhibit transformed properties that are hallmarks of leukemogenesis. These findings functionally link AML1 subnuclear targeting with competency for myeloid differentiation and expression of the transformed͞leukemia phenotype.acute myeloid leukemia ͉ AML1-ETO fusion protein ͉ nuclear matrix ͉ subnuclear organization C hanges in nuclear morphology are diagnostic hallmarks of leukemic cells and have been traditionally linked to structural and biochemical properties of hematopoietic lineage cells (1-3). In addition, the mammalian nucleus is functionally organized into subnuclear domains that contain regulatory machinery for transcription, replication, and repair (4-6). Alterations in the composition and distribution of these regulatory domains are observed in leukemic phenotypes (5, 7-9). Thus, modifications in nuclear structure and subnuclear organization are associated with normal myeloid cell growth͞differentiation and leukemic transformation.Acute myeloid leukemia (AML) is a prevalent hematopoietic malignancy characterized by abnormal proliferation and abrogated differentiation of myeloid progenitor cells (10, 11). Numerous cytogenetic abnormalities associated with AML involve the gene encoding acute myelogenous leukemia transcription factor 1 (AML1; also designated as Runt-related transcription factor 1, Runx1) (12, 13). AML1 is a nuclear matrix-associated transcription factor essential for hematopoiesis, thereby providing means to investigate nuclear structure-function interrelationships that are linked to biological control and are altered during disease (5, 14). For example, the (8;21) translocation, a predominant mutation identified in Ϸ15% of adult AML patients, produces a chimeric protein (AML1-ETO) in which the C terminus of AML1 is replaced by the ETO protein (13). The AML1-ETO translocation-fusion protein is a dominantnegative inhibitor of the endog...

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Cancer and the cell cycle

Cited by 69 publications

References 49 publications

The Hepatitis B Virus X Protein Modulates Hepatocyte Proliferation Pathways To Stimulate Viral Replication

The Hepatitis B Virus X Protein Modulates Hepatocyte Proliferation Pathways To Stimulate Viral Replication

Development of Cell-Cycle Inhibitors for Cancer Therapy

Point mutation in AML1 disrupts subnuclear targeting, prevents myeloid differentiation, and effects a transformation-like phenotype

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