Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins

Zancai, Paola; Col, Jessica Dal; Piccinin, Sara; Giusti, Massimo; Cariati, Roberta; Rizzo, Silvana; Boiocchi, Mauro; Maestro, Roberta; Dolcetti, Riccardo

doi:10.1038/sj.onc.1208458

Cited by 22 publications

(15 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[98][99][100][101][102][103][104][105] For example, similar to our studies, Oncostatin M, a potent growth inhibitor of different tumor cell types, overrode p27 destruction in S phase by accumulating p27 through the inhibition of Skp2 and Cks1 mRNA and protein. 103 Other studies show that the growth inhibitory and differentiation capacity of all-trans retinoic acid (ATRA) and retinoic acid is related to an increase in p27 due to ubiquitylation and degradation of Skp2 in breast cancer and lymphoblastoid cell lines.…”

Section: © 2 0 0 9 L a N D E S B I O S C I E N C E D O N O T D I S supporting

confidence: 86%

“…103 Other studies show that the growth inhibitory and differentiation capacity of all-trans retinoic acid (ATRA) and retinoic acid is related to an increase in p27 due to ubiquitylation and degradation of Skp2 in breast cancer and lymphoblastoid cell lines. 101,102 Since Skp2 binds to CRM1, it was suggested that Skp2 may mediate CRM1-dependent nuclear export of p27. 101 Thus, the downregulation of Skp2 by TGFβ may indeed retain p27 in the nucleus due to lack of CRM1 binding of p27 through Skp2.…”

Section: © 2 0 0 9 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

“…101,102 Since Skp2 binds to CRM1, it was suggested that Skp2 may mediate CRM1-dependent nuclear export of p27. 101 Thus, the downregulation of Skp2 by TGFβ may indeed retain p27 in the nucleus due to lack of CRM1 binding of p27 through Skp2. Similarly, vitamin D3 and analogues stabilized p27 by inhibiting mRNA synthesis of Skp2 and Cks1 and their binding to p27 in head and neck cancer cell lines; the presence of Skp2 and Cks1are poor prognostic markers for this cancer.…”

Section: © 2 0 0 9 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

See 2 more Smart Citations

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

Lecanda

Ganapathy²,

D'Aquino-Ardalan³

et al. 2009

Cell Cycle

View full text Add to dashboard Cite

TGFβ mediates cell cycle arrest in late G 1 phase of the cell cycle with a simultaneous peak in the levels of the cyclin-dependent kinase inhibitor, p27 kip1 (p27). In this report, we show that whereas p27 resides in the cytoplasm in the endometrial carcinoma (ECA) cell line HEC-1A, TGFβ increases the total levels and translocation of p27 into the nucleus. Concomitantly, TGFβ activates the transcription factors Smad2 and Smad3, inhibits proliferation, and blocks Cdk2 activity; all these events are blocked by an inhibitor of TβRI serine kinase activity (SD208). In addition, we show that inhibiting p27 transcription with a specific siRNA completely blocks TGFβ-mediated growth inhibition in these cells. These data suggest that TGFβ inhibits cellular proliferation by increasing p27 levels through Smad2/3 signaling in HEC-1A cells. We further show that TGFβ decreases the levels of components of the SCF Skp2 targeting complex for ubiquitin-mediated degradation of p27 in proteasomes, at the protein but not the mRNA level. Therefore, TGFβ accumulates nuclear p27 by preventing its degradation to enable G 1 arrest in HEC-1A cells. Importantly, these data suggest a novel mechanism for TGFβ/Smad mediated growth inhibition that might be inoperable in the numerous human cancers demonstrating early dysregulated TGFβ signaling and loss of growth inhibition. The TGFβ/p27 axis might provide novel therapeutic targets for cancer.

show abstract

Section: © 2 0 0 9 L a N D E S B I O S C I E N C E D O N O T D I S supporting

confidence: 86%

Section: © 2 0 0 9 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Section: © 2 0 0 9 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

See 1 more Smart Citation

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

Lecanda

Ganapathy²,

D'Aquino-Ardalan³

et al. 2009

Cell Cycle

View full text Add to dashboard Cite

show abstract

“…In fact, Spk2Ddb, but not wild-type Skp2, overexpression strongly prevented RA-induced cell cycle exit, as assessed by 5-bromo-2-deoxyuridine (BrdU) staining (Figure 2d), accumulation of p27 and Map2 (Figure 2e), and neurite outgrowth ( Figure 2f). These data are in good agreement with the recent work reporting p27 stabilization by proteasomedependent Skp2 degradation in cycling cancer cell lines (Zancai et al, 2005).…”

supporting

confidence: 93%

“…The stability of p27 is known to be regulated by the E3 ubiquitin ligase SCF (Skp1/Cul1/F-box) activator, Skp2, which targets p27 for ubiquitination and proteasomal degradation during late G 1 (Sheaff et al, 1997;Carrano et al, 1999;Sutterluty et al, 1999;Bloom and Pagano, 2003). Indeed, RA stabilizes p27 by enhancing proteasome-mediated degradation of Skp2 in several cancer cell lines (Dow et al, 2001;Nakamura et al, 2003;Zancai et al, 2005), although the molecular mechanism is still unknown. Here we have investigated how Skp2 affects the expression of p27 during RAmediated SH-SY5Y neuroblastoma cell cycle arrest, and the underlying mechanism.…”

mentioning

confidence: 99%

Retinoic acid downregulates Rae1 leading to APCCdh1 activation and neuroblastoma SH-SY5Y differentiation

et al. 2008

View full text Add to dashboard Cite

Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer

Hershko

2008

Cancer

169

153

View full text Add to dashboard Cite

The expression of Skp2, the ubiquitin ligase subunit that targets p27Kip1 for degradation, is commonly overexpressed in human cancers. p27Kip1 is a negative regulator of the cell cycle that plays an important role in tumor suppression. Loss of p27Kip1 secondary to enhanced ubiquitin‐mediated degradation results in uncontrolled proliferation and promotes tumor progression. In the present study the prognostic implications of Skp2 are reviewed and the mechanisms that regulate its expression in different human cancers. A review and analysis of the English literature was undertaken. Overexpression of Skp2 mRNA and protein levels was observed in many aggressive cancers and was commonly associated with down‐regulation of p27Kip1 levels and loss of tumor differentiation. Skp2 is an independent prognostic marker for disease‐free and overall survival and may provide additional predictive information to that provided by p27Kip1 alone. Targeting Skp2 in experimental models resulted in up‐regulation of p27Kip1 and arrested cellular proliferation. Alterations in Skp2 expression have profound effects on cancer progression and may serve as an accurate and independent prognostic marker. Thus, determination of levels of Skp2 and p27Kip1 by readily available immunohistochemical studies may be a useful tool in the assessment of prognosis, especially in patients with intermediate disease, and may potentially assist in the planning of adjuvant therapy. Skp2 may be an attractive target for the development of novel interventional therapy. Cancer 2008. © 2008 American Cancer Society.

show abstract

Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins

Cited by 22 publications

References 50 publications

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

Retinoic acid downregulates Rae1 leading to APCCdh1 activation and neuroblastoma SH-SY5Y differentiation

Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer

Contact Info

Product

Resources

About