Phosphorylation-Dependent Ubiquitination of Cyclin D1 by the SCFFBX4-αB Crystallin Complex

Lin, Douglas I.; Barbash, Olena; Kumar, Krishna; Weber, Jason D.; Harper, J. Wade; Klein‐Szanto, Andres J.; Rustgi, Anil K.; Fuchs, Serge Y.; Diehl, J. Alan

doi:10.1016/j.molcel.2006.09.007

Cited by 325 publications

(348 citation statements)

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“…Lack of both αA and αB-crystallin decreases the number of cells that enter the S phase during the cell cycle progression (Bai et al, 2004). Consistent with these studies, the association of αB-crystallin in a complex of FBX has been found to direct the ubiquitination of phosphorylated cyclin D1 during the cell cycle, signifying the importance of αB-crystallin in cell cycle regulation (Lin et al, 2006). Targeting key cell cycle regulatory molecules to the proteasome may be one of the functions of αB-crystallin in the lens epithelial growth control.…”

Section: Ensuring the Successful Completion Of Mitosis And Cytokinesissupporting

confidence: 64%

The lens epithelium: Focus on the expression and function of the α-crystallin chaperones

Andley

2008

The International Journal of Biochemistry & Cell Biology

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Lens epithelial cells are the parental cells responsible for growth and development of the transparent ocular lens. Many elegant investigations into their biology have focused on the factors that initiate and regulate lens epithelial cell differentiation. Because they serve key transport and cell maintenance functions throughout life, and are the primary source of metabolic activity in the lens, mechanisms to maintain lens epithelial cell integrity and survival are critical for lens transparency. The molecular chaperones α-crystallins are abundant proteins synthesized in the differentiated lens fiber cell cytoplasm. However, their expression in lens epithelial cells has only been appreciated very recently. Besides their important roles in the refractive and light focusing properties of the lens, α-crystallins have been implicated in a number of non-refractive pathways including those involving stress response, apoptosis and cell survival. The most convincing evidence for their importance in the lens epithelium has been shown by studies on the properties of lens epithelial cells from αA and αB-crystallin gene knockout mice. The effective combination of genetics, cell and molecular biology possible with lens epithelial cells is attracting an increasing number of researchers focused on understanding how lens epithelial cells coordinate survival, proliferation and differentiation. Cell facts• Lens epithelial cells are responsible for the growth and development of the entire ocular lens • Lens development is controlled by cell cycle regulators, signaling molecules and growth factors such as FGF • Lens epithelial cells express members of the small heat shock protein family of molecular chaperones, αA and βB-crystallins, the first crystallins to be expressed during lens development • α-Crystallins likely protect lens epithelial cells from environmental stress throughout life, and thus may delay the onset of age-related cataract • Lens epithelial cell proliferation is deregulated in posterior capsule opacification leading to secondary cataract, a complication in up to 50% of cataract surgeries Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

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Section: Ensuring the Successful Completion Of Mitosis And Cytokinesissupporting

confidence: 64%

The lens epithelium: Focus on the expression and function of the α-crystallin chaperones

Andley

2008

The International Journal of Biochemistry & Cell Biology

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“…Further studies are, however, warranted to address the possibilities that Erk, IkB kinase-a, and other kinases may also be involved in regulation of cyclin D2 expression through phosphorylation of Thr280. As very recent studies have revealed that ubiquitination of cyclin D1 phosphorylated on Thr286 is mediated by the Skp1-Cul1-F box (SCF) or SCF-like complexes where FBX4 as well as aB crystallin or FBXW8 governs substrate specificity (Lin et al, 2006;Okabe et al, 2006), future studies are also needed to identify the E3 ubiquitin ligase complexes involved in ubiquitination of cyclin D2 phosphorylated on Thr280.…”

Section: Discussionmentioning

confidence: 99%

Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

et al. 2007

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Cyclin D2 plays an important role in regulation of hematopoietic cell proliferation by cytokines and is implicated in oncogenesis of various hematopoietic malignancies. However, mechanisms regulating cyclin D2 stability and its expression level have remained to be known. Here, we demonstrate that interleukin-3 signaling stabilizes cyclin D2 by inhibition of glycogen synthase kinase-3b (GSK3b) through Janus kinase2-dependent activation of phosphatidylinositol 3 0 -kinase (PI3K)/Akt signaling pathway in hematopoietic 32Dcl3 cells. On the other hand, osmotic stress was shown to induce a rapid proteasomal degradation of cyclin D2, which was mediated by activation of p38. GSK3b and p38 was demonstrated to phosphorylate cyclin D2 on Thr280 in vitro, while a cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells. Inhibition of the PI3K pathway or induction of osmotic stress also caused a rapid proteasomal degradation of cyclin D2 in primary leukemic or myeloma cells. These results indicate that cyclin D2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by Thr280 phosphorylation by GSK3b or p38, which is induced by inhibition of the PI3K pathway or by osmotic stress, respectively.

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“…8,[10][11][12] One can predict that translation inhibition would consequently lead to downregulation of protein expression, particularly of those proteins having a short half-life such as CDK4, cyclin D and Cdc25. 1,[16][17][18][19] However, we noticed that Cdc25A was degraded upon Roc-A treatment with a much faster rate (with a half-life of less than 15 min) than Cdc25B, CDK4, CDK6 and cyclin D3 (Fig. 1g).…”

Section: Roc-a Suppresses Expression Of Key Proteins Involved In G1-smentioning

confidence: 93%

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATRChk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time-resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.In normal cells, the cell division cycle is tightly controlled. Cancer cells are characterized by deregulation in the cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. 1-3 Therefore, targeting the cancer cell cycle machinery has been considered to be a rational strategy for cancer treatment. 4 Cell division is governed by cyclin dependent kinases (CDKs) that are tightly regulated by cyclins and CDK inhibitors (CDKIs). Tumor-associated cell cycle defects often show alterations in CDK expression or/and activity. 2 Typically, CDK4 and CDK6 that are crucial for G1 checkpoint control are often over-expressed in many malignancies. 2,3 Evidence shows that deregulation of CDK4 and CDK6 activity is associated with a wide variety of tumors. 2 Moreover, elevated expressions of the cell division cycle 25 (Cdc25) phosphatases, in particular, the isoform Cdc25A, which is essential for cell cycle transitions of G1-S and S-G2, has been shown in different cancers and their over-expression often correlates with more aggressive disease and poor prognosis. 1,5 Recently, genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. 2 Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment.Rocaglamides (Roc; 5 Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals. A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the n...

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Phosphorylation-Dependent Ubiquitination of Cyclin D1 by the SCFFBX4-αB Crystallin Complex

Cited by 325 publications

References 48 publications

The lens epithelium: Focus on the expression and function of the α-crystallin chaperones

The lens epithelium: Focus on the expression and function of the α-crystallin chaperones

Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

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