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Titolo:
Histone acetylation and the cell-cycle in cancer
Autore:
Wang, CG; Fu, MF; Mani, S; Wadler, S; Senderowicz, AM; Pestell, RG;
Indirizzi:
Albert Einstein Coll Med, Dept Dev & Mol Biol, Albert Einstein Comprehens Canc Ctr, Bronx, NY 10461 USA Albert Einstein Coll Med Bronx NY USA 10461 Canc Ctr, Bronx, NY 10461 USA Natl Inst Dent & Craniofacial Res, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA Natl Inst Dent & Craniofacial Res Bethesda MD USA 20892 sda, MD 20892 USA
Titolo Testata:
FRONTIERS IN BIOSCIENCE
, volume: 6, anno: 2001,
pagine: D610 - D629
SICI:
1093-9946(200104)6:<D610:HAATCI>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-C; BREAST-CARCINOMA CELLS; MITOTIC CHROMOSOME CONDENSATION; HUMAN EPIDERMOID CARCINOMA; ELEMENT-BINDING PROTEIN; ACUTE MYELOID-LEUKEMIA; DEPENDENT KINASES; ESTROGEN-RECEPTOR; IN-VIVO; TRANSCRIPTIONAL REPRESSION;
Keywords:
histone acetyltransferases; cyclin-pendent kinase (Cdk) inhibitors; flavopiridol; UCN-01; anticancer agents; review;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
214
Recensione:
Indirizzi per estratti:
Indirizzo: Pestell, RG Albert Einstein Coll Med, Dept Dev & Mol Biol, Albert EinsteinComprehens Canc Ctr, Chanin 302,1300 Morris Pk Ave, Bronx, NY 10461 USA Albert Einstein Coll Med Chanin 302,1300 Morris Pk Ave Bronx NY USA 10461
Citazione:
C.G. Wang et al., "Histone acetylation and the cell-cycle in cancer", FRONT BIOSC, 6, 2001, pp. D610-D629

Abstract

A number of distinct surveillance systems are found in mammalian cells that have the capacity to interrupt normal cell-cycle progression. These are referred to as cell cycle check points. Surveillance systems activated by DNA damage act at three stages, one at the G(1)/S phase boundary, one that monitors progression through S phase and one at the G(2)/M boundary. The initiation of DNA synthesis and irrevocable progression through G(1) phase represents an additional checkpoint when the cell commits to DNA synthesis. Transition through the cell cycle is regulated by a family of protein kinase holoenzymes, the cyclin-dependent kinases (Cdks), and their heterodimeric cyclin partner. Orderly progression through the cell-cycle checkpoints involves coordinated activation of the Cdks that, in the presence of an associated Cdk-activating kinase (CAK), phosphorylate target substrates including members of the "pocket protein" family. One of these, the product of the retinoblastoma susceptibility gene (the pRB protein), is phosphorylated sequentially by both cyclin D/Cdk4 complexes and cyclin E/Cdk2 kinases. Recent studies have identified important cross talk between the cell-cycleregulatory apparatus and proteins regulating histone acetylation. pRB binds both E2F proteins and histone deacetylase (HDAC) complexes. HDAC plays animportant role in pRB tumor suppression function and transcriptional repression. Histones are required for accurate assembly of chromatin and the induction of histone gene expression is tightly coordinated. Recent studies have identified an important alternate substrate of cyclin E/Cdk2, NPAT (nuclear protein mapped to the ATM locus) which plays a critical role in promoting cell-cycle progression in the absence of pRB, and contributes to cell-cycle regulated histone gene expression. The acetylation of histones by a number of histone acetyl transferases (HATs) also plays an important role in coordinating gene expression and cell-cycle progression. Components of the cell-cycle regulatory apparatus are both regulated by HATs and bind directlyto HATs. Finally transcription factors have been identified as substrate for HATs. Mutations of these transcription factors at their sites of acetylation has been associated with constitutive activity and enhanced cellular proliferation, suggesting an important role for acetylation in transcriptional repression as well as activation. Together these studies provide a working model in which the cell-cycle regulatory kinases phosphorylate and inactivate HDACs, coordinate histone gene expression and bind to histone acetylases themselves. The recent evidence for cross-talk between the cyclin-dependent kinases and histone gene expression on the one hand and cyclin-dependent regulation of histone acetylases on the other, suggests chemotherapeutics targeting histone acetylation may have complex and possibly complementaryeffects with agents targeting Cdks.

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Documento generato il 15/01/21 alle ore 23:20:08