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Article: Bone marrow stromal cells reduce low-dose cytarabine-induced differentiation of acute myeloid leukemia.

Smoljo, Tomislav / Tomic, Barbara / Lalic, Hrvoje / Dembitz, Vilma / Batinic, Josip / Bedalov, Antonio / Visnjic, Dora

2023 Volume 14, Page(s) 1258151

Abstract: Low-dose cytarabine (LDAC) is a standard therapy for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. While high doses of cytarabine induce cytotoxicity, the precise mechanism of action of LDAC in AML remains elusive. ...

Abstract	Low-dose cytarabine (LDAC) is a standard therapy for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. While high doses of cytarabine induce cytotoxicity, the precise mechanism of action of LDAC in AML remains elusive.
Language	English
Publishing date	2023-10-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1258151
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Article ; Online: AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review.

Višnjić, Dora / Lalić, Hrvoje / Dembitz, Vilma / Tomić, Barbara / Smoljo, Tomislav

Cells

2021 Volume 10, Issue 5

Abstract: 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr) has been one of the most commonly used pharmacological modulators of AMPK activity. The majority of early studies on the role of AMPK, both in the physiological regulation of metabolism and in cancer ... ...

Abstract	5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr) has been one of the most commonly used pharmacological modulators of AMPK activity. The majority of early studies on the role of AMPK, both in the physiological regulation of metabolism and in cancer pathogenesis, were based solely on the use of AICAr as an AMPK-activator. Even with more complex models of AMPK downregulation and knockout being introduced, AICAr remained a regular starting point for many studies focusing on AMPK biology. However, there is an increasing number of studies showing that numerous AICAr effects, previously attributed to AMPK activation, are in fact AMPK-independent. This review aims to give an overview of the present knowledge on AMPK-dependent and AMPK-independent effects of AICAr on metabolism, hypoxia, exercise, nucleotide synthesis, and cancer, calling for caution in the interpretation of AICAr-based studies in the context of understanding AMPK signaling pathway.
MeSH term(s)	Aminoimidazole Carboxamide/analogs & derivatives ; Aminoimidazole Carboxamide/pharmacology ; Animals ; Carcinogenesis/drug effects ; Cell Cycle/drug effects ; Energy Metabolism/drug effects ; Humans ; Hypoglycemic Agents/pharmacology ; Myocytes, Cardiac/drug effects ; Protein Kinases/metabolism ; Ribonucleotides/pharmacology
Chemical Substances	Hypoglycemic Agents ; Ribonucleotides ; Aminoimidazole Carboxamide (360-97-4) ; Protein Kinases (EC 2.7.-) ; AMP-activated protein kinase kinase (EC 2.7.1.-) ; AICA ribonucleotide (F0X88YW0YK)
Language	English
Publishing date	2021-05-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Systematic Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10051095
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Article ; Online: Bendamustine: A review of pharmacology, clinical use and immunological effects (Review).

Lalic, Hrvoje / Aurer, Igor / Batinic, Drago / Visnjic, Dora / Smoljo, Tomislav / Babic, Antonija

Oncology reports

2022 Volume 47, Issue 6

Abstract: Bendamustine is an alkylating agent classified into the group of nitrogen mustard analogues, synthesized almost sixty years ago. It was registered in former East Germany in 1971 and approved by the US Food and Drug Administration in 2008 for treatment of ...

Abstract	Bendamustine is an alkylating agent classified into the group of nitrogen mustard analogues, synthesized almost sixty years ago. It was registered in former East Germany in 1971 and approved by the US Food and Drug Administration in 2008 for treatment of chronic lymphocytic leukemia and indolent B‑cell non‑Hodgkin lymphoma. Considering its beneficial properties in the therapy of relapsed or refractory hematological malignancies, synergistic effects with other antineoplastic agents and increasing recent reports on its immunomodulatory effects, bendamustine has once again gained its justified attention. The uniqueness of bendamustine‑mediated effects should be observed keeping in mind its distinctive structure with structural similarities to both alkylating agents and purine analogs. In the present review, the current knowledge on the use of bendamustine in oncology, its pharmacokinetics, mechanism of action and toxicity was summarized. In addition, its immune‑modulating effects that have not been fully elucidated so far are emphasized, hoping to encourage further investigations of this unique drug.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Bendamustine Hydrochloride/pharmacology ; Bendamustine Hydrochloride/therapeutic use ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Lymphoma, B-Cell/drug therapy ; Nitrogen Mustard Compounds/chemistry ; Nitrogen Mustard Compounds/pharmacology ; Nitrogen Mustard Compounds/therapeutic use
Chemical Substances	Antineoplastic Agents ; Nitrogen Mustard Compounds ; Bendamustine Hydrochloride (981Y8SX18M)
Language	English
Publishing date	2022-05-04
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	1222484-4
ISSN	1791-2431 ; 1021-335X
ISSN (online)	1791-2431
ISSN	1021-335X
DOI	10.3892/or.2022.8325
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Article ; Online: The Role of AMPK/mTOR Modulators in the Therapy of Acute Myeloid Leukemia.

Visnjic, Dora / Dembitz, Vilma / Lalic, Hrvoje

Current medicinal chemistry

2018 Volume 26, Issue 12, Page(s) 2208–2229

Abstract: Differentiation therapy of acute promyelocytic leukemia with all-trans retinoic acid represents the most successful pharmacological therapy of acute myeloid leukemia (AML). Numerous studies demonstrate that drugs that inhibit mechanistic target of ... ...

Abstract	Differentiation therapy of acute promyelocytic leukemia with all-trans retinoic acid represents the most successful pharmacological therapy of acute myeloid leukemia (AML). Numerous studies demonstrate that drugs that inhibit mechanistic target of rapamycin (mTOR) and activate AMP-kinase (AMPK) have beneficial effects in promoting differentiation and blocking proliferation of AML. Most of these drugs are already in use for other purposes; rapalogs as immunosuppressants, biguanides as oral antidiabetics, and 5-amino-4-imidazolecarboxamide ribonucleoside (AICAr, acadesine) as an exercise mimetic. Although most of these pharmacological modulators have been widely used for decades, their mechanism of action is only partially understood. In this review, we summarize the role of AMPK and mTOR in hematological malignancies and discuss the possible role of pharmacological modulators in proliferation and differentiation of leukemia cells.
MeSH term(s)	AMP-Activated Protein Kinases/antagonists & inhibitors ; AMP-Activated Protein Kinases/chemistry ; AMP-Activated Protein Kinases/metabolism ; Aminoimidazole Carboxamide/analogs & derivatives ; Aminoimidazole Carboxamide/metabolism ; Aminoimidazole Carboxamide/therapeutic use ; Clinical Trials as Topic ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Metformin/metabolism ; Metformin/therapeutic use ; RNA, Small Interfering/metabolism ; RNA, Small Interfering/therapeutic use ; Ribonucleosides/metabolism ; Ribonucleosides/therapeutic use ; Signal Transduction/drug effects ; Sirolimus/analogs & derivatives ; Sirolimus/metabolism ; Sirolimus/therapeutic use ; TOR Serine-Threonine Kinases/chemistry ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	RNA, Small Interfering ; Ribonucleosides ; Aminoimidazole Carboxamide (360-97-4) ; acadesine (53IEF47846) ; Metformin (9100L32L2N) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2018-01-18
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	1319315-6
ISSN	1875-533X ; 0929-8673
ISSN (online)	1875-533X
ISSN	0929-8673
DOI	10.2174/0929867325666180117105522
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Article ; Online: Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis.

Tomic, Barbara / Smoljo, Tomislav / Lalic, Hrvoje / Dembitz, Vilma / Batinic, Josip / Batinic, Drago / Bedalov, Antonio / Visnjic, Dora

Scientific reports

2022 Volume 12, Issue 1, Page(s) 11344

Abstract: Acute myeloid leukemia (AML) is characterized by arrested differentiation making differentiation therapy a promising treatment strategy. Recent success of inhibitors of mutated isocitrate dehydrogenase (IDH) invigorated interest in differentiation ... ...

Abstract	Acute myeloid leukemia (AML) is characterized by arrested differentiation making differentiation therapy a promising treatment strategy. Recent success of inhibitors of mutated isocitrate dehydrogenase (IDH) invigorated interest in differentiation therapy of AML so that several new drugs have been proposed, including inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme in pyrimidine synthesis. Cytarabine, a backbone of standard AML therapy, is known to induce differentiation at low doses, but the mechanism is not completely elucidated. We have previously reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) and brequinar, a DHODH inhibitor, induced differentiation of myeloid leukemia by activating the ataxia telangiectasia and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) via pyrimidine depletion. In this study, using immunoblotting, flow cytometry analyses, pharmacologic inhibitors and genetic inactivation of Chk1 in myeloid leukemia cell lines, we show that low dose cytarabine induces differentiation by activating Chk1. In addition, cytarabine induces differentiation ex vivo in a subset of primary AML samples that are sensitive to AICAr and DHODH inhibitor. The results of our study suggest that leukemic cell differentiation stimulated by low doses of cytarabine depends on the activation of Chk1 and thus shares the same pathway as pyrimidine synthesis inhibitors.
MeSH term(s)	Cell Differentiation ; Checkpoint Kinase 1/metabolism ; Cytarabine/pharmacology ; Cytarabine/therapeutic use ; Dihydroorotate Dehydrogenase ; Enzyme Inhibitors/pharmacology ; Humans ; Leukemia, Myeloid, Acute/genetics ; Pyrimidines/therapeutic use
Chemical Substances	Dihydroorotate Dehydrogenase ; Enzyme Inhibitors ; Pyrimidines ; Cytarabine (04079A1RDZ) ; Checkpoint Kinase 1 (EC 2.7.11.1)
Language	English
Publishing date	2022-07-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-15520-z
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Article: 5-Aminoimidazole-4-carboxamide ribonucleoside-induced autophagy flux during differentiation of monocytic leukemia cells.

Dembitz, Vilma / Lalic, Hrvoje / Visnjic, Dora

Cell death discovery

2017 Volume 3, Page(s) 17066

Abstract: Pharmacological modulators of AMP-dependent kinase (AMPK) have been suggested in treatment of cancer. The biguanide metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) have been reported to inhibit proliferation of solid tumors and ... ...

Abstract	Pharmacological modulators of AMP-dependent kinase (AMPK) have been suggested in treatment of cancer. The biguanide metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) have been reported to inhibit proliferation of solid tumors and hematological malignancies, but their role in differentiation is less explored. Our previous study demonstrated that AICAR alone induced AMPK-independent expression of differentiation markers in monocytic U937 leukemia cells, and no such effects were observed in response to metformin. The aim of this study was to determine the mechanism of AICAR-mediated effects and to test for the possible role of autophagy in differentiation of leukemia cells. The results showed that AICAR-mediated effects on the expression of differentiation markers were not mimicked by A769662, a more specific direct AMPK activator. Long-term incubation of U937 cells with AICAR and other differentiation agents, all-
Language	English
Publishing date	2017-10-02
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/cddiscovery.2017.66
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Article ; Online: All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16.

Dembitz, Vilma / Lalic, Hrvoje / Tomic, Barbara / Smoljo, Tomislav / Batinic, Josip / Dubravcic, Klara / Batinic, Drago / Bedalov, Antonio / Visnjic, Dora

International journal of hematology

2021 Volume 115, Issue 1, Page(s) 43–53

Abstract: All-trans retinoic acid (ATRA)-based therapy for acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), is the most successful example of differentiation therapy. Although ATRA can induce differentiation in some non-APL AML cell ... ...

Abstract	All-trans retinoic acid (ATRA)-based therapy for acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), is the most successful example of differentiation therapy. Although ATRA can induce differentiation in some non-APL AML cell lines and primary blasts, clinical results of adding ATRA to standard therapy in non-APL AML patients have been inconsistent, probably due to use of different regimens and lack of diagnostic tools for identifying which patients may be sensitive to ATRA. In this study, we exposed primary blasts obtained from non-APL AML patients to ATRA to test for differentiation potential in vitro. We observed increased expression of differentiation markers, indicating a response to ATRA, in four out of fifteen primary AML samples. Three samples in which CD11b increased in response to ATRA had an inversion of chromosome 16 as well as the CBFB-MYH11 fusion gene, and the fourth sample was from a patient with KMT2A-rearranged, therapy-related AML. In conclusion, we identified a subgroup of non-APL AML patients with inv(16) and CBFB-MYH11 as the most sensitive to ATRA-mediated differentiation in vitro, and our results can help identify patients who may benefit from ATRA treatment.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Blast Crisis/genetics ; Blast Crisis/pathology ; CD11b Antigen/metabolism ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Chromosome Inversion/genetics ; Chromosomes, Human, Pair 16/genetics ; Core Binding Factor beta Subunit/genetics ; Gene Fusion/drug effects ; Gene Rearrangement/genetics ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Myeloid-Lymphoid Leukemia Protein/genetics ; Myosin Heavy Chains/genetics ; Tretinoin/pharmacology ; Tretinoin/therapeutic use
Chemical Substances	Antineoplastic Agents ; CD11b Antigen ; Core Binding Factor beta Subunit ; ITGAM protein, human ; KMT2A protein, human ; MYH11 protein, human ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Tretinoin (5688UTC01R) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Myosin Heavy Chains (EC 3.6.4.1)
Language	English
Publishing date	2021-09-21
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1076875-0
ISSN	1865-3774 ; 0917-1258 ; 0925-5710
ISSN (online)	1865-3774
ISSN	0917-1258 ; 0925-5710
DOI	10.1007/s12185-021-03224-5
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Article ; Online: The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 via pyrimidine depletion.

Dembitz, Vilma / Tomic, Barbara / Kodvanj, Ivan / Simon, Julian A / Bedalov, Antonio / Visnjic, Dora

The Journal of biological chemistry

2019 Volume 294, Issue 42, Page(s) 15257–15270

Abstract: Metabolic pathways play important roles in proliferation and differentiation of malignant cells. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr), a precursor in purine biosynthesis and a well-established activator of AMP-activated protein kinase ( ... ...

Abstract	Metabolic pathways play important roles in proliferation and differentiation of malignant cells. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr), a precursor in purine biosynthesis and a well-established activator of AMP-activated protein kinase (AMPK), induces widespread metabolic alterations and is commonly used for dissecting the role of metabolism in cancer. We have previously reported that AICAr promotes differentiation and inhibits proliferation of myeloid leukemia cells. Here, using metabolic assays, immunoblotting, flow cytometry analyses, and siRNA-mediated gene silencing in leukemia cell lines, we show that AICAr-mediated differentiation was independent of the known metabolic effects of AMPK, including glucose consumption, but instead depends on the activation of the DNA damage-associated enzyme checkpoint kinase 1 (Chk1) induced by pyrimidine depletion. LC/MS/MS metabolomics analysis revealed that AICAr increases orotate levels and decreases uridine monophosphate (UMP) levels, consistent with inhibition of UMP synthesis at a step downstream of dihydroorotate dehydrogenase (DHODH). AICAr and the DHODH inhibitor brequinar had similar effects on differentiation markers and S-phase arrest, and genetic or pharmacological Chk1 inactivation abrogated both of these effects. Our results delineate an AMPK-independent effect of AICAr on myeloid leukemia differentiation that involves perturbation of pyrimidine biosynthesis and activation of the DNA damage response network.
MeSH term(s)	AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Aminoimidazole Carboxamide/analogs & derivatives ; Aminoimidazole Carboxamide/metabolism ; Cell Differentiation ; Cell Line, Tumor ; Checkpoint Kinase 1/genetics ; Checkpoint Kinase 1/metabolism ; Humans ; Leukemia, Promyelocytic, Acute/genetics ; Leukemia, Promyelocytic, Acute/metabolism ; Leukemia, Promyelocytic, Acute/physiopathology ; Oxidoreductases Acting on CH-CH Group Donors/genetics ; Oxidoreductases Acting on CH-CH Group Donors/metabolism ; Pyrimidines/metabolism ; Ribonucleosides/genetics ; Ribonucleosides/metabolism ; S Phase Cell Cycle Checkpoints
Chemical Substances	Pyrimidines ; Ribonucleosides ; Aminoimidazole Carboxamide (360-97-4) ; acadesine (53IEF47846) ; Oxidoreductases Acting on CH-CH Group Donors (EC 1.3.-) ; dihydroorotate dehydrogenase (EC 1.3.5.2) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; pyrimidine (K8CXK5Q32L)
Language	English
Publishing date	2019-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA119.009396
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Article ; Online: 5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts.

Dembitz, Vilma / Lalic, Hrvoje / Kodvanj, Ivan / Tomic, Barbara / Batinic, Josip / Dubravcic, Klara / Batinic, Drago / Bedalov, Antonio / Visnjic, Dora

BMC cancer

2020 Volume 20, Issue 1, Page(s) 1090

Abstract: Background: All-trans retinoic acid (ATRA)-based treatment of acute promyelocytic leukemia (APL) is the most successful pharmacological treatment of acute myeloid leukemia (AML). Recent development of inhibitors of mutated isocitrate dehydrogenase and ... ...

Abstract	Background: All-trans retinoic acid (ATRA)-based treatment of acute promyelocytic leukemia (APL) is the most successful pharmacological treatment of acute myeloid leukemia (AML). Recent development of inhibitors of mutated isocitrate dehydrogenase and dihydroorotate dehydrogenase (DHODH) has revived interest in differentiation therapy of non-APL AML. Our previous studies demonstrated that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induced differentiation of monocytic cell lines by activating the ATR/Chk1 via pyrimidine depletion. In the present study, the effects of AICAr on the viability and differentiation of primary AML blasts isolated from bone marrow of patients with non-APL AML were tested and compared with the effects of DHODH inhibitor brequinar and ATRA. Methods: Bone marrow samples were obtained from 35 patients and leukemia blasts were cultured ex vivo. The cell viability was assessed by MTT assay and AML cell differentiation was determined by flow cytometry and morphological analyses. RNA sequencing and partial data analysis were conducted using ClusterProfiler package. Statistical analysis was performed using GraphPad Prism 6.0. Results: AICAr is capable of triggering differentiation in samples of bone marrow blasts cultured ex vivo that were resistant to ATRA. AICAr-induced differentiation correlates with proliferation and sensitivity to DHODH inhibition. RNA-seq data obtained in primary AML blasts confirmed that AICAr treatment induced downregulation of pyrimidine metabolism pathways together with an upregulation of gene set involved in hematopoietic cell lineage. Conclusion: AICAr induces differentiation in a subset of primary non-APL AML blasts, and these effects correlate with sensitivity to a well-known, potent DHODH inhibitor.
MeSH term(s)	Aminoimidazole Carboxamide/analogs & derivatives ; Aminoimidazole Carboxamide/pharmacology ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Blast Crisis/drug therapy ; Blast Crisis/genetics ; Blast Crisis/metabolism ; Blast Crisis/pathology ; Bone Marrow/drug effects ; Bone Marrow/metabolism ; Bone Marrow/pathology ; Case-Control Studies ; Cell Differentiation ; Cell Proliferation ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; RNA-Seq ; Ribonucleosides/pharmacology ; Tumor Cells, Cultured
Chemical Substances	Biomarkers, Tumor ; Ribonucleosides ; Aminoimidazole Carboxamide (360-97-4) ; acadesine (53IEF47846)
Language	English
Publishing date	2020-11-11
Publishing country	England
Document type	Journal Article
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-020-07533-6
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Article: Nuclear phospholipid signaling: phosphatidylinositol-specific phospholipase C and phosphoinositide 3-kinase.

Visnjic, Dora / Banfic, Hrvoje

Pflugers Archiv : European journal of physiology

2007 Volume 455, Issue 1, Page(s) 19–30

Abstract: Over the last 20 years, numerous studies have demonstrated the existence of nuclear phosphoinositide signaling distinct from the one at the plasma membrane. The activation of phosphatidylinositol-specific phospholipase C (PI-PLC) and phosphoinositide 3- ... ...

Abstract	Over the last 20 years, numerous studies have demonstrated the existence of nuclear phosphoinositide signaling distinct from the one at the plasma membrane. The activation of phosphatidylinositol-specific phospholipase C (PI-PLC) and phosphoinositide 3-kinase (PI3K), the generation of diacylglycerol, and the accumulation of the 3-phosphorylated phosphoinositides have been documented in the nuclei of different cell types. In this review, we summarize some recent studies of the subnuclear localization, mechanisms of activation, and the possible physiological roles of the nuclear PI-PLC and PI-3 kinases in the regulation of cell cycle, survival, and differentiation.
MeSH term(s)	Animals ; Cell Cycle/physiology ; Cell Differentiation/physiology ; Cell Nucleus/enzymology ; Cell Nucleus/physiology ; Humans ; Mitosis/physiology ; Phosphatidylinositol 3-Kinases/physiology ; Phosphoinositide Phospholipase C/physiology ; Phospholipids/physiology ; Signal Transduction/physiology
Chemical Substances	Phospholipids ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Phosphoinositide Phospholipase C (EC 3.1.4.11)
Language	English
Publishing date	2007-06-09
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-007-0288-1
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