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256


Role of Cks1 overexpression in oral squamous cell carcinomas: cooperation with Skp2 in promoting p27 degradation

Kitajima, Shojiro; Kudo, Yasusei; Ogawa, Ikuko; Bashir, Tarig; Kitagawa, Masae; Miyauchi, Mutsumi; Pagano, Michele; Takata, Takashi
Down-regulation of p27 is frequently observed in various cancers due to an enhancement of its degradation. Skp2 is required for the ubiquitination and consequent degradation of p27 protein. Another protein called Cks1 is also required for p27 ubiquitination in the SCF(Skp2) ubiquitinating machinery. In the present study, we examined Cks1 expression and its correlation with p27 in oral squamous cell carcinoma (OSCC) derived from tongue and gingiva. By immunohistochemical analysis, high expression of Cks1 was present in 62% of OSCCs in comparison with 0% of normal mucosae. In addition, 65% of samples with low p27 expression displayed high Cks1 levels. Finally, Cks1 expression was well correlated with Skp2 expression and poor prognosis. To study the role of Cks1 overexpression in p27 down-regulation, we transfected Cks1 with or without Skp2 into OSCC cells. Cks1 transfection could not induce a p27 down-regulation by itself, but both Cks1 and Skp2 transfection strongly induced. Moreover, we inhibited Cks1 expression by small interference RNA (siRNA) in OSCC. Cks1 siRNA transfection induced p27 accumulation and inhibited the growth of OSCC cells. These findings suggest that Cks1 overexpression may play an important role for OSCC development through Skp2-mediated p27 degradation, and that Cks1 siRNA can be a novel modality of gene therapy
PMCID:1618711
PMID: 15579456
ISSN: 0002-9440
CID: 64219

Cell cycle, proteolysis and cancer

Yamasaki, Lili; Pagano, Michele
Research in the past 15 years has shown that the mammalian cell cycle is controlled by the action of cyclin-dependent kinases (CDKs). A crucial substrate of the CDKs in G1-phase is the retinoblastoma tumor suppressor (pRB), which restrains proliferation largely by repressing the activity of the E2F transcription factors. More recent work has shown that the cell cycle is also a tale of two classes of ubiquitin ligases, referred to as SCF and APC/C ligases. CDKs, E2F and ubiquitin ligases reciprocally regulate each other, resulting in complex feedback loops. Perturbation of this network of molecular machines is associated with proliferative diseases, including cancer
PMID: 15530772
ISSN: 0955-0674
CID: 64221

Varshavsky's contributions [Letter]

Baumeister, Wolfgang; Bachmair, Andreas; Chau, Vincent; Cohen, Robert; Coffino, Phil; Demartino, George; Deshaies, Raymond; Dohmen, Juergen; Emr, Scott; Finley, Daniel; Hampton, Randy; Hill, Christopher; Hochstrasser, Mark; Huber, Robert; Jackson, Peter; Jentsch, Stefan; Johnson, Erica; Kwon, Yong Tae; Pagano, Michele; Pickart, Cecile; Rechsteiner, Martin; Scheffner, Martin; Sommer, Thomas; Tansey, William; Tyers, Mike; Vierstra, Richard; Weissman, Allan; Wilkinson, Keith D; Wolf, Dieter
PMID: 15550643
ISSN: 1095-9203
CID: 64220

Systematic analysis and nomenclature of mammalian F-box proteins [Letter]

Jin, Jianping; Cardozo, Timothy; Lovering, Ruth C; Elledge, Stephen J; Pagano, Michele; Harper, J Wade
PMCID:525538
PMID: 15520277
ISSN: 0890-9369
CID: 64222

An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant

Ji, Peng; Jiang, Hong; Rekhtman, Katya; Bloom, Joanna; Ichetovkin, Marina; Pagano, Michele; Zhu, Liang
It is believed that Rb blocks G1-S transition by inhibiting expression of E2F regulated genes. Here, we report that the effects of E2F repression lag behind the onset of G1 cell cycle arrest in timed Rb reexpression experiments. In comparison, kinase inhibitor p27Kip1 protein accumulates with a faster kinetics. Conversely, Rb knockout leads to faster p27 degradation. Rb interacts with the N terminus of Skp2, interferes with Skp2-p27 interaction, and inhibits ubiquitination of p27. Disruption of p27 function or expression of the Skp2 N terminus prevents Rb from causing G1 arrest. A full-penetrance, inactive Rb mutant fails to interfere with Skp2-p27 interaction but, interestingly, a partial-penetrance Rb mutant that is defective for E2F binding retains full activity in inhibiting Skp2-p27 interaction and can induce G1 cell cycle arrest with wild-type kinetics. These results identify an Rb-Skp2-p27 pathway in Rb function, which may be involved in inhibition of tumor progression
PMID: 15469821
ISSN: 1097-2765
CID: 64223

Wagging the dogma; tissue-specific cell cycle control in the mouse embryo

Pagano, Michele; Jackson, Peter K
The family of cyclin-dependent kinases (Cdks) lies at the core of the machinery that drives the cell division cycle. Studies in cultured mammalian cells have provided insight into the cellular functions of many Cdks. Recent Cdk and cyclin knockouts in the mouse show that the functions of G1 cell cycle regulatory genes are often essential only in specific cell types, pointing to our limited understanding of tissue-specific expression, redundancy, and compensating mechanisms in the Cdk network
PMID: 15339658
ISSN: 0092-8674
CID: 45026

The SCF ubiquitin ligase: insights into a molecular machine

Cardozo, Timothy; Pagano, Michele
Ubiquitin ligases are well suited to regulate molecular networks that operate on a post-translational timescale. The F-box family of proteins - which are the substrate-recognition components of the Skp1-Cul1-F-box-protein (SCF) ubiquitin ligase - are important players in many mammalian functions. Here we explore a unifying and structurally detailed view of SCF-mediated proteolytic control of cellular processes that has been revealed by recent studies
PMID: 15340381
ISSN: 1471-0072
CID: 45024

Role of F-Box Protein betaTrcp1 in mammary gland development and tumorigenesis

Kudo, Yasusei; Guardavaccaro, Daniele; Santamaria, Patricia G; Koyama-Nasu, Ryo; Latres, Esther; Bronson, Roderick; Yamasaki, Lili; Pagano, Michele
The F-box protein betaTrcp1 controls the stability of several crucial regulators of proliferation and apoptosis, including certain inhibitors of the NF-kappaB family of transcription factors. Here we show that mammary glands of betaTrcp1(-/-) female mice display a hypoplastic phenotype, whereas no effects on cell proliferation are observed in other somatic cells. To investigate further the role of betaTrcp1 in mammary gland development, we generated transgenic mice expressing human betaTrcp1 targeted to epithelial cells under the control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. Compared to controls, MMTV betaTrcp1 mammary glands display an increase in lateral ductal branching and extensive arrays of alveolus-like protuberances. The mammary epithelia of MMTV betaTrcp1 mice proliferate more and show increased NF-kappaB DNA binding activity and higher levels of nuclear NF-kappaB p65/RelA. In addition, 38% of transgenic mice develop tumors, including mammary, ovarian, and uterine carcinomas. The targeting of betaTrcp1 to lymphoid organs produces no effects on these tissues. In summary, our results support the notion that betaTrcp1 positively controls the proliferation of breast epithelium and indicate that alteration of betaTrcp1 function and expression may contribute to malignant behavior of breast tumors, at least in part through NF-kappaB transactivation
PMCID:515055
PMID: 15340078
ISSN: 0270-7306
CID: 45025

Don't skip the G(1) phase: How APC/C(Cdh1) Keeps SCF(Skp2) in Check

Bashir, Tarig; Pagano, Michele
By keeping the levels of Skp2 and Cks1 low during G(1) progression, APC/C(Cdh1) prevents unscheduled degradation of SCF(Skp2) substrates and premature entry into S phase. Thus, APC/C(Cdh1), a ubiquitin ligase involved in mitotic exit and maintenance of G(0)/G(1) phase, directly controls SCF(Skp2), a ubiquitin ligase involved in the regulation of S phase entry
PMID: 15190201
ISSN: 1538-4101
CID: 44902

Ubiquitin-dependent degradation of p73 is inhibited by PML

Bernassola, Francesca; Salomoni, Paolo; Oberst, Andrew; Di Como, Charles J; Pagano, Michele; Melino, Gerry; Pandolfi, Pier Paolo
p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin-proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML-nuclear body (NB)-dependent manner. p38 mitogen-activated protein kinase-mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml-/- primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression
PMCID:2211783
PMID: 15184504
ISSN: 0022-1007
CID: 45027