scholarly journals Cdc53p acts in concert with Cdc4p and Cdc34p to control the G1-to-S-phase transition and identifies a conserved family of proteins.

1996 ◽  
Vol 16 (12) ◽  
pp. 6634-6643 ◽  
Author(s):  
N Mathias ◽  
S L Johnson ◽  
M Winey ◽  
A E Adams ◽  
L Goetsch ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Large Family ◽  
S Phase ◽  
Genetic Interactions ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Ubiquitin Conjugating Enzyme ◽  
Regulation Of Cell Cycle

Regulation of cell cycle progression occurs in part through the targeted degradation of both activating and inhibitory subunits of the cyclin-dependent kinases. During G1, CDC4, encoding a WD-40 repeat protein, and CDC34, encoding a ubiquitin-conjugating enzyme, are involved in the destruction of these regulators. Here we describe evidence indicating that CDC53 also is involved in this process. Mutations in CDC53 cause a phenotype indistinguishable from those of cdc4 and cdc34 mutations, numerous genetic interactions are seen between these genes, and the encoded proteins are found physically associated in vivo. Cdc53p defines a large family of proteins found in yeasts, nematodes, and humans whose molecular functions are uncharacterized. These results suggest a role for this family of proteins in regulating cell cycle proliferation through protein degradation.

scholarly journals The Ubc3 (Cdc34) ubiquitin-conjugating enzyme is ubiquitinated and phosphorylated in vivo.

1994 ◽  
Vol 14 (5) ◽  
pp. 3022-3029 ◽  
Author(s):  
M G Goebl ◽  
L Goetsch ◽  
B Byers
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Protein S ◽  
S Phase ◽  
Cycle Progression ◽  
Endogenous Protein ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzyme

The transition from G1 to S phase of the cell cycle in Saccharomyces cerevisiae requires the activity of the Ubc3 (Cdc34) ubiquitin-conjugating enzyme. S. cerevisiae cells lacking a functional UBC3 (CDC34) gene are able to execute the Start function that initiates the cell cycle but fail to form a mitotic spindle or enter S phase. The Ubc3 (Cdc34) enzyme has previously been shown to catalyze the attachment of multiple ubiquitin molecules to model substrates, suggesting that the role of this enzyme in cell cycle progression depends on its targeting an endogenous protein(s) for degradation. In this report, we demonstrate that the Ubc3 (Cdc34) protein is itself a substrate for both ubiquitination and phosphorylation. Immunochemical localization of the gene product to the nucleus renders it likely that the relevant substrates similarly reside within the nucleus.

scholarly journals Phosphorylation-induced unfolding regulates p19INK4dduring the human cell cycle

2018 ◽  
Vol 115 (13) ◽  
pp. 3344-3349 ◽  
Author(s):  
Amit Kumar ◽  
Mohanraj Gopalswamy ◽  
Annika Wolf ◽  
David J. Brockwell ◽  
Mechthild Hatzfeld ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Structural Biology ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Ankyrin Repeat Protein ◽  
Dependent Protein ◽  
Local Unfolding ◽  
Molecular Mode

Cell cycle progression is tightly regulated by cyclin-dependent kinases (CDKs). The ankyrin-repeat protein p19INK4dfunctions as a key regulator of G1/S transition; however, its molecular mode of action is unknown. Here, we combine cell and structural biology methods to unravel the mechanism by which p19INK4dcontrols cell cycle progression. We delineate how the stepwise phosphorylation of p19INK4dSer66 and Ser76 by cell cycle-independent (p38) and -dependent protein kinases (CDK1), respectively, leads to local unfolding of the three N-terminal ankyrin repeats of p19INK4d. This dissociates the CDK6–p19INK4dinhibitory complex and, thereby, activates CDK6. CDK6 triggers entry into S-phase, whereas p19INK4dis ubiquitinated and degraded. Our findings reveal how signaling-dependent p19INK4dunfolding contributes to the irreversibility of G1/S transition.

scholarly journals Association of human ubiquitin-conjugating enzyme CDC34 with the mitotic spindle in anaphase

2000 ◽  
Vol 113 (10) ◽  
pp. 1687-1694 ◽  
Author(s):  
F. Reymond ◽  
C. Wirbelauer ◽  
W. Krek
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Mitotic Spindle ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Intracellular Localization ◽  
Cycle Progression ◽  
Ubiquitin Conjugating Enzyme ◽  
Regulation Of Cell Cycle ◽  
Conjugating Enzyme

Present in organisms ranging from yeast to man, homologues of the Saccharomyces cerevisiae ubiquitin-conjugating enzyme CDC34 have been shown to play important roles in the regulation of cell cycle progression and checkpoint function. Here we analyze the expression and intracellular localization of endogenous CDC34 during mammalian cell cycle progression. We find that CDC34 protein is constitutively expressed during all stages of the cell cycle. Immunofluorescence experiments reveal that during interphase, endogenous CDC34 is localized to distinct speckles in both the nucleus and the cytoplasm. The presence of CDC34 in these compartments has also been established by biochemical fractionation experiments. Interestingly, nuclear localization depends on the presence of specific carboxy-terminal CDC34 sequences that have previously been shown to be required for CDC34's cell cycle function in Saccharomyces cerevisiae. Finally, we find that in anaphase and not during early stages of mitosis, CDC34 colocalizes with (beta)-tubulin at the mitotic spindle, implying that it may contribute to spindle function at later stages of mitosis. Taken together, these results support a model in which CDC34 ubiquitin-conjugating enzyme functions in the regulation of nuclear and cytoplasmic activities as well as in the process of chromosome segregation at the onset of anaphase in mammalian cells.

Chemical fragment-based CDK4/6 inhibitors prediction and web server

RSC Advances ◽  
2016 ◽  
Vol 6 (21) ◽  
pp. 16972-16981 ◽  
Author(s):  
Ling Wang ◽  
Yecheng Li ◽  
Mengyan Xu ◽  
Xiaoqian Pang ◽  
Zhihong Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Neuronal Differentiation ◽  
Cell Cycle Progression ◽  
Web Server ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Regulation Of Cell Cycle

Cyclin-dependent kinases (CDKs), a family of mammalian heterodimeric kinases, play central roles in the regulation of cell cycle progression, transcription, neuronal differentiation, and metabolism.

E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 886-895 ◽  
Author(s):  
Kathryn M. Kinross ◽  
Allison J. Clark ◽  
Rosa M. Iazzolino ◽  
Patrick Orson Humbert
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Cell Cycle Control ◽  
Macrocytic Anemia ◽  
Cycle Progression ◽  
Promote Cell Cycle Progression ◽  
Regulation Of Cell Cycle ◽  
Fetal Erythropoiesis

Abstract The E2F proteins are major regulators of the transcriptional program required to coordinate cell cycle progression and exit. In particular, E2f4 has been proposed to be the principal family member responsible for the regulation of cell cycle exit chiefly through its transcriptional repressive properties. We have previously shown that E2f4–/– mice display a marked macrocytic anemia implicating E2f4 in the regulation of erythropoiesis. However, these studies could not distinguish whether E2f4 was required for differentiation, survival, or proliferation control. Here, we describe a novel function for E2f4 in the promotion of erythroid proliferation. We show that loss of E2f4 results in an impaired expansion of the fetal erythroid compartment in vivo that is associated with impaired cell cycle progression and decreased erythroid proliferation. Consistent with these observations, cDNA microarray analysis reveals cell cycle control genes as one of the major class of genes down-regulated in E2f4–/– FLs, and we provide evidence that E2f4 may directly regulate the transcriptional expression of a number of these genes. We conclude that the macrocytic anemia of E2f4–/– mice results primarily from impaired cellular proliferation and that the major role of E2f4 in fetal erythropoiesis is to promote cell cycle progression and cellular proliferation.

scholarly journals Blocking the transcription factor E2F/DP by dominant-negative mutants in a normal breast epithelial cell line efficiently inhibits apoptosis and induces tumor growth in SCID mice.

1996 ◽  
Vol 183 (3) ◽  
pp. 1205-1213 ◽  
Author(s):  
R C Bargou ◽  
C Wagener ◽  
K Bommert ◽  
W Arnold ◽  
P T Daniel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Dominant Negative ◽  
Serum Starvation ◽  
Cycle Progression ◽  
Transcription Factor E2f

The transcription factor E2F is regulated during the cell cycle through interactions with the product of the retinoblastoma susceptibility gene and related proteins. It is thought that E2F-mediated gene regulation at the G1/S boundary and during S phase may be one of the rate-limiting steps in cell proliferation. It was reported that in vivo overexpression of E2F-1 in fibroblasts induces S phase entry and leads to apoptosis. This observation suggests that E2F plays a role in both cell cycle regulation and apoptosis. To further understand the role of E2F in cell cycle progression, cell death, and tumor development, we have blocked endogenous E2F activity in HBL-100 cells, derived from nonmalignant human breast epithelium, using dominant-negative mutants under the control of a tetracycline-dependent expression system. We have shown here that induction of dominant-negative mutants led to strong downregulation of transiently transfected E2F-dependent chloramphenicol acetyl transferase reporter constructs and of endogenous c-myc, which has been described as a target gene of the transcription factor E2F/DP. In addition, we have shown that blocking of E2F could efficiently protect from apoptosis induced by serum starvation within a period of 10 d, whereas control cells started to die after 24 h. Surprisingly, blocking of E2F did not alter the rate of proliferation or of DNA synthesis of these cells; this finding indicates that cell-cycle progression could be driven in an E2F-independent manner. In addition, we have been able to show that blocking of endogenous E2F in HBL-100 cells led to rapid induction of tumor growth in severe combined immunodeficiency mice. No tumor growth could be observed in mice that received mock-transfected clones or tetracycline to block expression of the E2F mutant constructs in vivo. Thus, it appears that E2F has a potential tumor-suppressive function under certain circumstances. Furthermore, we provide evidence that dysregulation of apoptosis may be an important step in tumorigenesis.

scholarly journals Disruption of the Rb-Raf-1 Interaction Inhibits Tumor Growth and Angiogenesis

2004 ◽  
Vol 24 (21) ◽  
pp. 9527-9541 ◽  
Author(s):  
Piyali Dasgupta ◽  
Jiazhi Sun ◽  
Sheng Wang ◽  
Gina Fusaro ◽  
Vicki Betts ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Mitogen Activated Protein Kinase ◽  
Tubule Formation ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Quiescent Cells ◽  
Stimulation Of

ABSTRACT The retinoblastoma tumor suppressor protein (Rb) plays a vital role in regulating mammalian cell cycle progression and inactivation of Rb is necessary for entry into S phase. Rb is inactivated by phosphorylation upon growth factor stimulation of quiescent cells, facilitating the transition from G1 phase to S phase. Although the signaling events after growth factor stimulation have been well characterized, it is not yet clear how these signals contact the cell cycle machinery. We had found previously that growth factor stimulation of quiescent cells lead to the direct binding of Raf-1 kinase to Rb, leading to its inactivation. Here we show that the Rb-Raf-1 interaction occurs prior to the activation of cyclin and/or cyclin-dependent kinases and facilitates normal cell cycle progression. Raf-1-mediated inactivation of Rb is independent of the mitogen-activated protein kinase cascade, as well as cyclin-dependent kinases. Binding of Raf-1 seemed to correlate with the dissociation of the chromatin remodeling protein Brg1 from Rb. Disruption of the Rb-Raf-1 interaction by a nine-amino-acid peptide inhibits Rb phosphorylation, cell proliferation, and vascular endothelial growth factor-mediated capillary tubule formation. Delivery of this peptide by a carrier molecule led to a 79% reduction in tumor volume and a 57% reduction in microvessel formation in nude mice. It appears that Raf-1 links mitogenic signaling to Rb and that disruption of this interaction could aid in controlling proliferative disorders.

scholarly journals Core Control Principles of the Eukaryotic Cell Cycle

2021 ◽  
Author(s):  
Souradeep Basu ◽  
Paul Nurse ◽  
Andrew Jones
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Eukaryotic Cell ◽  
Protein Phosphatase 1 ◽  
Cycle Progression ◽  
Substrate Specificities ◽  
Cyclin Dependent Kinases ◽  
Do So

Abstract Cyclin dependent kinases (CDKs) lie at the heart of eukaryotic cell cycle control, with different Cyclin-CDK complexes initiating DNA replication (S-CDKs) and mitosis (M-CDKs). However, the principles on which Cyclin-CDKs organise the temporal order of cell cycle events are contentious. The currently most widely accepted model, is that the S-CDKs and M-CDKs are functionally specialised, with significant different substrate specificities to execute different cell cycle events. A second model is that S-CDKs and M-CDKs are redundant with each other, with both acting as sources of overall cellular CDK activity. Here we reconcile these two views of core cell cycle control. Using a multiplexed phosphoproteomics assay of in vivo S-CDK and M-CDK activities in fission yeast, we show that S-CDK and M-CDK substrate specificities are very similar, showing that S-CDKs are not completely specialised for S-phase alone. Normally S-CDK cannot undergo mitosis, but is able to do so when Protein Phosphatase 1 (PP1) is removed from the centrosome, allowing several mitotic substrates to be better phosphorylated by S-CDK in vivo. Thus, an increase in S-CDK activity in vivo is sufficient to allow S-CDK to carry out M-CDK function. Therefore, we unite the two opposing views of cell cycle control, showing that the core cell cycle engine which temporally orders cell cycle progression is largely based upon a quantitative increase of CDK activity through the cell cycle, combined with minor qualitative differences in catalytic specialisation of S-CDKs and M-CDKs.

scholarly journals NPAT Expression Is Regulated by E2F and Is Essential for Cell Cycle Progression

2003 ◽  
Vol 23 (8) ◽  
pp. 2821-2833 ◽  
Author(s):  
Guang Gao ◽  
Adrian P. Bracken ◽  
Karina Burkard ◽  
Diego Pasini ◽  
Marie Classon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Histone Gene ◽  
Cycle Progression ◽  
Histone Gene Transcription ◽  
E2f Proteins ◽  
Phase Entry

ABSTRACT NPAT is an in vivo substrate of cyclin E-Cdk2 kinase and is thought to play a critical role in coordinated transcriptional activation of histone genes during the G1/S-phase transition and in S-phase entry in mammalian cells. Here we show that NPAT transcription is up-regulated at the G1/S-phase boundary in growth-stimulated cells and that the NPAT promoter responds to activation by E2F proteins. We demonstrate that endogenous E2F proteins interact with the promoter of the NPAT gene in vivo and that induced expression of E2F1 stimulates NPAT mRNA expression, supporting the idea that the expression of NPAT is regulated by E2F. Consistently, we find that the E2F sites in the NPAT promoter are required for its activation during the G1/S-phase transition. Moreover, we show that the expression of NPAT accelerates S-phase entry in cells released from quiescence. The inhibition of NPAT expression by small interfering RNA duplexes impedes cell cycle progression and histone gene expression in tissue culture cells. Thus, NPAT is an important E2F target that is required for cell cycle progression in mammalian cells. As NPAT is involved in the regulation of S-phase-specific histone gene transcription, our findings indicate that NPAT links E2F to the activation of S-phase-specific histone gene transcription.

scholarly journals The Role of Non-Coding RNAs in Controlling Cell Cycle Related Proteins in Cancer Cells

2020 ◽  
Vol 10 ◽  
Author(s):  
Soudeh Ghafouri-Fard ◽  
Hamed Shoorei ◽  
Farhad Tondro Anamag ◽  
Mohammad Taheri
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Human Disorders ◽  
Non Coding Rnas ◽  
Regulation Of Cell Cycle ◽  
Related Proteins ◽  
Regulate Cell Cycle Progression

Cell cycle is regulated by a number of proteins namely cyclin-dependent kinases (CDKs) and their associated cyclins which bind with and activate CDKs in a phase specific manner. Additionally, several transcription factors (TFs) such as E2F and p53 and numerous signaling pathways regulate cell cycle progression. Recent studies have accentuated the role of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in the regulation of cell cycle. Both lncRNAs and miRNAs interact with TFs participating in the regulation of cell cycle transition. Dysregulation of cell cycle regulatory miRNAs and lncRNAs results in human disorders particularly cancers. Understanding the role of lncRNAs, miRNAs, and TFs in the regulation of cell cycle would pave the way for design of anticancer therapies which intervene with the cell cycle progression. In the current review, we describe the role of lncRNAs and miRNAs in the regulation of cell cycle and their association with human malignancies.

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