scholarly journals In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials

2006 ◽  
Vol 5 (11) ◽  
pp. 2644-2658 ◽  
Author(s):  
Wanda DePinto ◽  
Xin-Jie Chu ◽  
Xuefeng Yin ◽  
Melissa Smith ◽  
Kathryn Packman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Phase I Clinical Trials ◽  
Cyclin Dependent Kinase Inhibitor

scholarly journals Negative Regulation of ASK1 by p21Cip1 Involves a Small Domain That Includes Serine 98 That Is Phosphorylated by ASK1 In Vivo

2007 ◽  
Vol 27 (9) ◽  
pp. 3530-3541 ◽  
Author(s):  
Jun Zhan ◽  
John B. Easton ◽  
Shile Huang ◽  
Ashutosh Mishra ◽  
Limin Xiao ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cellular Functions ◽  
Terminal Protein ◽  
Jnk Pathway ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Small Domain ◽  
Cellular Stresses

ABSTRACT The cyclin-dependent kinase inhibitor p21Cip1 regulates multiple cellular functions and protects cells from genotoxic and other cellular stresses. Activation of apoptosis signal-regulating kinase 1 (ASK1) induced by inhibition of mTOR signaling leads to sustained phospho-c-Jun that is suppressed in cells with functional p53 or by forced expression of p21Cip1. Here we show that small deletions of p21Cip1 around S98 abrogate its association with ASK1 but do not affect binding to Cdk1, hence distinguishing between the cell cycle-regulating functions of p21Cip1 and its ability to suppress activation of the ASK1/Jun N-terminal protein kinase (JNK) pathway. p21Cip1 is phosphorylated in vitro by both ASK1 and JNK1 at S98. In vivo phosphorylation of p21Cip1, predominantly carried out by ASK1, is associated with binding to ASK1 and inactivation of ASK1 kinase function. Binding of p21Cip1 to ASK1 requires ASK1 kinase function and may involve phosphorylation of S98.

scholarly journals Antitumor effects of flavopiridol, a cyclin-dependent kinase inhibitor, on human cholangiocarcinoma in vitro and in an in vivo xenograft model

Heliyon ◽  
2019 ◽  
Vol 5 (5) ◽  
pp. e01675 ◽  
Author(s):  
Saowaluk Saisomboon ◽  
Ryusho Kariya ◽  
Kulthida Vaeteewoottacharn ◽  
Sopit Wongkham ◽  
Kanlayanee Sawanyawisuth ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Xenograft Model ◽  
Cyclin Dependent Kinase ◽  
Antitumor Effects ◽  
Cyclin Dependent Kinase Inhibitor

scholarly journals Susceptibility of cyclin-dependent kinase inhibitor 1-deficient mice to rheumatoid arthritis arising from interleukin-1β-induced inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoshinori Takashima ◽  
Shinya Hayashi ◽  
Koji Fukuda ◽  
Toshihisa Maeda ◽  
Masanori Tsubosaka ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Cartilage Destruction ◽  
Cyclin Dependent Kinase ◽  
In Vivo Models ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Tnf Α ◽  
Safranin O ◽  
And Cartilage

AbstractWe recently reported that cyclin-dependent kinase inhibitor 1 (p21) deficiency induces osteoarthritis susceptibility. Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21−/−) (n = 16) and wild type C57BL/6 (p21+/+) mice (n = 16) served as in vivo models of collagen antibody-induced arthritis (CAIA). Arthritis severity was evaluated by immunological and histological analyses. The response of p21 small-interfering RNA (siRNA)-treated human RA FLSs (n = 5 per group) to interleukin (IL)-1β stimulation was determined in vitro. Arthritis scores were higher in p21−/− mice than in p21+/+ mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21−/− mice compared to p21+/+ mice. p21−/− mice expressed higher levels of IL-1β, TNF-α, F4/80, CD86, p-IKKα/β, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKα/β and IκBα phosphorylation in human FLSs. p21-deficient CAIA mice are susceptible to RA phenotype alterations, including joint cartilage destruction and severe synovitis. Therefore, p21 may have a regulatory role in inflammatory cytokine production including IL-1β, IL-6, and TNF-α.

scholarly journals p27Kip1 and p130 Cooperate To Regulate Hematopoietic Cell Proliferation In Vivo

2006 ◽  
Vol 26 (16) ◽  
pp. 6170-6184 ◽  
Author(s):  
Inês Soeiro ◽  
Azim Mohamedali ◽  
Hanna M. Romanska ◽  
Nicholas C. Lea ◽  
Emma S. Child ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kinase Inhibitor ◽  
Hematopoietic Cell ◽  
Molecular Evidence ◽  
Cyclin Dependent Kinase ◽  
Erythroid Progenitors ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Bona Fide

ABSTRACT To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27 Kip1 −/−; p130 −/− mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27 Kip1 −/− counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27 Kip1 −/−; p130 −/− animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27 Kip1 −/− splenocytes. The finding that the p27 Kip1 −/−; p130 −/− splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27Kip1 to regulate hematopoietic cell proliferation in vivo.

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

2011 ◽  
Vol 30 (3) ◽  
pp. 889-897 ◽  
Author(s):  
Xiangrui Liu ◽  
Frankie Lam ◽  
Shenhua Shi ◽  
Peter M. Fischer ◽  
Shudong Wang
Keyword(s):  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor
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