scholarly journals Regulation of CDK7–Carboxyl-Terminal Domain Kinase Activity by the Tumor Suppressor p16INK4A Contributes to Cell Cycle Regulation

2000 ◽  
Vol 20 (20) ◽  
pp. 7726-7734 ◽  
Author(s):  
Eiji Nishiwaki ◽  
Saralinda L. Turner ◽  
Susanna Harju ◽  
Shiro Miyazaki ◽  
Masahide Kashiwagi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Rna Polymerase Ii ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Alternative Pathway ◽  
Cycle Progression ◽  
Terminal Domain ◽  
Carboxyl Terminal Domain ◽  
Carboxyl Terminal

ABSTRACT The eukaryotic cell cycle is regulated by cyclin-dependent kinases (CDKs). CDK4 and CDK6, which are activated by D-type cyclins during the G1 phase of the cell cycle, are thought to be responsible for phosphorylation of the retinoblastoma gene product (pRb). The tumor suppressor p16INK4A inhibits phosphorylation of pRb by CDK4 and CDK6 and can thereby block cell cycle progression at the G1/S boundary. Phosphorylation of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II by general transcription factor TFIIH is believed to be an important regulatory event in transcription. TFIIH contains a CDK7 kinase subunit and phosphorylates the CTD. We have previously shown that p16INK4A inhibits phosphorylation of the CTD by TFIIH. Here we report that the ability of p16INK4A to inhibit CDK7-CTD kinase contributes to the capacity to induce cell cycle arrest. These results suggest that p16INK4A may regulate cell cycle progression by inhibiting not only CDK4-pRb kinase activity but also by modulating CDK7-CTD kinase activity. Regulation of CDK7-CTD kinase activity by p16INK4A thus may represent an alternative pathway for controlling cell cycle progression.

scholarly journals The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death

Oncogene ◽  
1999 ◽  
Vol 18 (37) ◽  
pp. 5239-5245 ◽  
Author(s):  
Karen E Knudsen ◽  
Erich Weber ◽  
Karen C Arden ◽  
Webster K Cavenee ◽  
James R Feramisco ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Cycle Progression ◽  
Retinoblastoma Tumor Suppressor ◽  
Retinoblastoma Tumor

Pyk2 and FAK differentially regulate progression of the cell cycle

2000 ◽  
Vol 113 (17) ◽  
pp. 3063-3072 ◽  
Author(s):  
J. Zhao ◽  
C. Zheng ◽  
J. Guan
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Expression System ◽  
Chimeric Protein ◽  
Kinase Domain ◽  
Cycle Progression ◽  
Erk Activation ◽  
Terminal Domain ◽  
Cycle Regulation

We have previously identified FAK and its associated signaling pathways as a mediator of cell cycle progression by integrins. In this report, we have analyzed the potential role and mechanism of Pyk2, a tyrosine kinase closely related to FAK, in cell cycle regulation by using tetracycline-regulated expression system as well as chimeric molecules. We have found that induction of Pyk2 inhibited G(1) to S phase transition whereas comparable induction of FAK expression accelerated it. Furthermore, expression of a chimeric protein containing Pyk2 N-terminal and kinase domain and FAK C-terminal domain (PFhy1) increased cell cycle progression as FAK. Conversely, the complementary chimeric molecule containing FAK N-terminal and kinase domain and Pyk2 C-terminal domain (FPhy2) inhibited cell cycle progression to an even greater extent than Pyk2. Biochemical analyses indicated that Pyk2 and FPhy2 stimulated JNK activation whereas FAK or PFhy1 had little effect on it, suggesting that differential activation of JNK by Pyk2 may contribute to its inhibition of cell cycle progression. In addition, Pyk2 and FPhy2 to a greater extent also inhibited Erk activation in cell adhesion whereas FAK and PFhy1 stimulated it, suggesting a role for Erk activation in mediating differential regulation of cell cycle by Pyk2 and FAK. A role for Erk and JNK pathways in mediating the cell cycle regulation by FAK and Pyk2 was also confirmed by using chemical inhibitors for these pathways. Finally, we showed that while FAK and PFhy1 were present in focal contacts, Pyk2 and FPhy2 were localized in the cytoplasm. Interestingly, both Pyk2 and FPhy2 (to a greater extent) were tyrosine phosphorylated and associated with Src and Fyn. This suggested that they may inhibit Erk activation in an analogous manner as the mislocalized FAK mutant (Δ)C14 described previously by competing with endogenous FAK for binding signaling molecules such as Src and Fyn. This model is further supported by an inhibition of endogenous FAK association with active Src by Pyk2 and FPhy2 and a partial rescue by FAK of Pyk2-mediated cell cycle inhibition.

scholarly journals Mutagenesis of ARS2 Domains To Assess Possible Roles in Cell Cycle Progression and MicroRNA and Replication-Dependent Histone mRNA Biogenesis

2015 ◽  
Vol 35 (21) ◽  
pp. 3753-3767 ◽  
Author(s):  
Connor O'Sullivan ◽  
Jennifer Christie ◽  
Marcus Pienaar ◽  
Jake Gambling ◽  
Philip E. B. Nickerson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Rna Polymerase Ii ◽  
Cell Cycle Progression ◽  
Rna Recognition Motif ◽  
Rna Recognition ◽  
Histone Mrna ◽  
Cycle Progression ◽  
Transcript Processing ◽  
C Terminus ◽  
Domain Of Unknown Function

ARS2 is a regulator of RNA polymerase II transcript processing through its role in the maturation of distinct nuclear cap-binding complex (CBC)-controlled RNA families. In this study, we examined ARS2 domain function in transcript processing. Structural modeling based on the plant ARS2 orthologue, SERRATE, revealed 2 previously uncharacterized domains in mammalian ARS2: an N-terminal domain of unknown function (DUF3546), which is also present in SERRATE, and an RNA recognition motif (RRM) that is present in metazoan ARS2 but not in plants. Both the DUF3546 and zinc finger domain (ZnF) were required for association with microRNA and replication-dependent histone mRNA. Mutations in the ZnF disrupted interaction with FLASH, a key component in histone pre-mRNA processing. Mutations targeting the Mid domain implicated it in DROSHA interaction and microRNA biogenesis. The unstructured C terminus was required for interaction with the CBC protein CBP20, while the RRM was required for cell cycle progression and for binding to FLASH. Together, our results support a bridging model in which ARS2 plays a central role in RNA recognition and processing through multiple protein and RNA interactions.

scholarly journals Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity

Development ◽  
2001 ◽  
Vol 128 (9) ◽  
pp. 1687-1696 ◽  
Author(s):  
K. Halfar ◽  
C. Rommel ◽  
H. Stocker ◽  
E. Hafen
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Photoreceptor Cells ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Partial Loss ◽  
Cycle Progression ◽  
Mapk Activity ◽  
Dividing Cells

Ras mediates a plethora of cellular functions during development. In the developing eye of Drosophila, Ras performs three temporally separate functions. In dividing cells, it is required for growth but is not essential for cell cycle progression. In postmitotic cells, it promotes survival and subsequent differentiation of ommatidial cells. In the present paper, we have analyzed the different roles of Ras during eye development by using molecularly defined complete and partial loss-of-function mutations of Ras. We show that the three different functions of Ras are mediated by distinct thresholds of MAPK activity. Low MAPK activity prolongs cell survival and permits differentiation of R8 photoreceptor cells while high or persistent MAPK activity is sufficient to precociously induce R1-R7 photoreceptor differentiation in dividing cells.

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