Farnesyl Transferase Inhibitors Block the Farnesylation of CENP-E and CENP-F and Alter the Association of CENP-E with the Microtubules

Ashar, Hena R.; James, Linda; Gray, Kimberly; Carr, Donna; Black, Stuart; Armstrong, Lydia; Bishop, W. Robert; Kirschmeier, Paul T.

doi:10.1074/jbc.m003469200

Cited by 314 publications

(275 citation statements)

References 47 publications

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“…CaaX proteins that are processed by these enzymes have a variety of final intracellular localizations. For instance, Ras is located at the plasma membrane and endomembranes (Choy et al, 1999), Pex19 resides in the peroxisomal membrane (Gotte et al, 1998), and lamins and CENP-F are nuclear proteins (Liao et al, 1995;Ashar et al, 2000;Gruenbaum et al, 2005). Although it is possible that prelamin A and/or lamin B undergo processing in the cytosol and at the ER, followed by import into the nucleus via the nuclear localization sequence (NLS; Figure 1B, left), there is evidence to suggest that nuclear lamins may be an exception and that lamin A processing occurs within the nucleus ( Figure 1B, right).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

Barrowman¹,

Hamblet²,

George³

et al. 2008

MBoC

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Proteins establish and maintain a distinct intracellular localization by means of targeting, retention, and retrieval signals, ensuring most proteins reside predominantly in one cellular location. The enzymes involved in the maturation of lamin A present a challenge to this paradigm. Lamin A is first synthesized as a 74-kDa precursor, prelamin A, with a C-terminal CaaX motif and undergoes a series of posttranslational modifications including CaaX processing (farnesylation, aaX cleavage and carboxylmethylation), followed by endoproteolytic cleavage by Zmpste24. Failure to cleave prelamin A results in progeria and related premature aging disorders. Evidence suggests prelamin A is imported directly into the nucleus where it is processed. Paradoxically, the processing enzymes have been shown to reside in the cytosol (farnesyltransferase), or are ER membrane proteins (Zmpste24, Rce1, and Icmt) with their active sites facing the cytosol. Here we have reexamined the cellular site of prelamin A processing, and show that the mammalian and yeast processing enzymes Zmpste24 and Icmt exhibit a dual localization to the inner nuclear membrane, as well as the ER membrane. Our findings reveal the nucleus to be a physiologically relevant location for CaaX processing, and provide insight into the biology of a protein at the center of devastating progeroid diseases. INTRODUCTIONThe nuclear envelope consists of an inner and outer membrane. The outer nuclear membrane (ONM) is continuous with the endoplasmic reticulum (ER) and connects with the inner nuclear membrane (INM) at the nuclear pore membrane (POM; Lusk et al., 2007). Integral membrane proteins that reside in the INM are initially inserted into the endoplasmic reticulum (ER) membrane and move via the POM to the INM where they maintain a concentrated localization by binding to chromatin or tethering to the nuclear lamina (Powell and Burke, 1990;Soullam and Worman, 1993;Holmer and Worman, 2001;Ohba et al., 2004;Lusk et al., 2007;Schirmer and Foisner, 2007). Until recently, conventional wisdom held that the localization of proteins to either the ER membrane or the INM is mutually exclusive. For example, proteins that are found within the INM, such as LAP1, are not generally found throughout the ER/ONM; likewise, ER proteins such as HMG-CoA reductase are strictly localized to the ER (Wright et al., 1988;Powell and Burke, 1990;Deng and Hochstrasser, 2006). It was recently shown that a notable exception to this paradigm is the yeast E3 ubiquitin ligase, Doa10p. Doa10p was long known to reside in the ER membrane (Swanson et al., 2001;Kreft et al., 2006). However, recent data indicate that Doa10p exhibits dual steady-state localizations, residing and functioning in both the ER membrane where it mediates ER-associated degradation of membrane and secretory proteins, and in the INM where it mediates degradation of the nuclear transcription factor MAT␣2 (Deng and Hochstrasser, 2006).The present study documents another exception to the mutual exclusivity of ER membrane and INM localizati...

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Section: Introductionmentioning

confidence: 99%

Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

Barrowman¹,

Hamblet²,

George³

et al. 2008

MBoC

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“…Indeed, such an inhibitor is being evaluated currently in multiple clinical trials for the treatment of solid tumors. 75,76 However, once CENP-E expression is altered in cells, the chromosomes cannot separate normally, and this may result in aneuploidy, which is a hallmark in most solid cancers, such as hepatocellular carcinoma (HCC). 77 Liu et al 78 observed that CENP-E expression was reduced in HCC tissue, and low CENP-E expression resulted in aneuploidy in the normal liver cell line LO2.…”

Section: Kinesin-7 Familymentioning

confidence: 99%

The role of kinesin family proteins in tumorigenesis and progression

Feng

2010

Cancer

113

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The kinesin superfamily contains a conserved class of microtubule-dependent molecular motor proteins that possess an adenosine triphosphatase activity and motion characteristics. The active movement of kinesins supports several cellular functions, including mitosis, meiosis, and the transport of macromolecules. Mitosis is a process of eukaryotic cell division that involves the division of nuclei, cytoplasm, organelles, and the cell membrane into 2 daughter cells with roughly equivalent portions of these cellular components. Any errors in this process could result in cell death, abnormality (such as gene deletion, chromosome translocation, or duplication), and cancer. Because mitosis is complex and highly regulated, alteration of kinesin expression or function could lead to carcinogenesis. Moreover, because human cancer is a gene-related disease involving abnormal cell growth, targeting kinesins may create a novel strategy for the control of human cancer. Indeed, several such drugs are being tested successfully in the clinic. In this review, the authors discuss in detail the structure and function of kinesins, the correlation of kinesin expression with tumorigenesis and progression, and the development of biomarkers and cancer-targeted therapy involving the kinesin family proteins. Cancer 2010;116:5150-60.

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“…The combined ether extracts were dried over Na 2 SO 4 and solvent was removed. The residue was chromatographed to give 495 mg (78 %) of a colorless oil; 1 …”

Section: Methodsmentioning

confidence: 99%

“…The chloride was then treated with (NBu 4 ) 3 HP 2 O 7 .3H 2 O (1.65 g, 1.68 mmol), and the product was purified as described to give 127 mg (53 %) of a white solid; 1 …”

Section: Decadienyl Azide Diphosphate 3-oppmentioning

confidence: 99%

Farnesyl Diphosphate Analogues with ω-Bioorthogonal Azide and Alkyne Functional Groups for Protein Farnesyl Transferase-Catalyzed Ligation Reactions

2007

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Eleven farnesyl diphosphate analogues, which contained ω-azide or alkyne substituents suitable for bioorthogonal Staudinger and Huisgen [3+2] cycloaddition coupling reactions, were synthesized. The analogues were evaluated as substrates for alkylation of peptide co-substrates by yeast protein farnesyl transferase. Five of the diphosphates were good alternative substrates for FPP. Steady-state kinetic constants were measured for the active compounds, and the products were characterized by HPLC and LC-Mass. Two of the analogues gave steady state kinetic parameters (k cat and K M ) very similar to those of the natural substrate.

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Farnesyl Transferase Inhibitors Block the Farnesylation of CENP-E and CENP-F and Alter the Association of CENP-E with the Microtubules

Cited by 314 publications

References 47 publications

Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

The role of kinesin family proteins in tumorigenesis and progression

Farnesyl Diphosphate Analogues with ω-Bioorthogonal Azide and Alkyne Functional Groups for Protein Farnesyl Transferase-Catalyzed Ligation Reactions

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