The Cyclin-dependent Kinase Cdk2 Regulates Thymocyte Apoptosis

Aberrant activation of cell cycle molecules has been postulated to play a role in apoptosis (“catastrophic cell cycle”). Here we show that in noncycling developing thymocytes, the cyclin- dependent kinase Cdk2 is activated in response to all specific and nonspecific apoptotic stimuli tested, including peptide-specific thymocyte apoptosis. Cdk2 was found to function upstream of the tumor suppressor p53, transactivation of the death promoter Bax, alterations of mitochondrial permeability, Bcl-2, caspase activation, and caspase-dependent proteolytic cleavage of the retinoblastoma protein. Inhibition of Cdk2 completely protected thymocytes from apoptosis, mitochondrial changes, and caspase activation. These data provide the first evidence that Cdk2 activity is crucial for the induction of thymocyte apoptosis.

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P21 and Retinoblastoma Protein Control the Absence of DNA Replication in Terminally Differentiated Muscle Cells

The Journal of Cell Biology ◽

10.1083/jcb.149.2.281 ◽

2000 ◽

Vol 149 (2) ◽

pp. 281-292 ◽

Cited By ~ 51

Author(s):

Asoke Mal ◽

Debasis Chattopadhyay ◽

Mrinal K. Ghosh ◽

Randy Y.C. Poon ◽

Tony Hunter ◽

...

Keyword(s):

Cell Cycle ◽

Dna Replication ◽

Retinoblastoma Protein ◽

Muscle Cells ◽

Cyclin Dependent Kinase ◽

Adenovirus E1a ◽

Protein Levels ◽

Quiescent Cells ◽

Cdk2 Activity ◽

Multinucleated Myotubes

During differentiation, skeletal muscle cells withdraw from the cell cycle and fuse into multinucleated myotubes. Unlike quiescent cells, however, these cells cannot be induced to reenter S phase by means of growth factor stimulation. The studies reported here document that both the retinoblastoma protein (Rb) and the cyclin-dependent kinase (cdk) inhibitor p21 contribute to this unresponsiveness. We show that the inactivation of Rb and p21 through the binding of the adenovirus E1A protein leads to the induction of DNA replication in differentiated muscle cells. Moreover, inactivation of p21 by E1A results in the restoration of cyclin E–cdk2 activity, a kinase made nonfunctional by the binding of p21 and whose protein levels in differentiated muscle cells is relatively low in amount. We also show that restoration of kinase activity leads to the phosphorylation of Rb but that this in itself is not sufficient for allowing differentiated muscle cells to reenter the cell cycle. All the results obtained are consistent with the fact that Rb is functioning downstream of p21 and that the activities of these two proteins may be linked in sustaining the postmitotic state.

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The Sumoylation Modulated Tumor Suppressor p53 Regulates Cell Cycle Checking Genes to Mediate Lens Differentiation

Current Molecular Medicine ◽

10.2174/1566524019666190111154450 ◽

2019 ◽

Vol 18 (8) ◽

pp. 556-565 ◽

Cited By ~ 1

Author(s):

Xiangcheng Tang ◽

Zhigang Chen ◽

Mi Deng ◽

Ling Wang ◽

Qian Nie ◽

...

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Tumor Suppressor P53

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Cell cycle function of a Medicago sativa A2-type cyclin interacting with a PSTAIRE-type cyclin-dependent kinase and a retinoblastoma protein

The Plant Journal ◽

10.1046/j.1365-313x.2000.00794.x ◽

2000 ◽

Vol 23 (1) ◽

pp. 73-83 ◽

Cited By ~ 52

Author(s):

Francois Roudier ◽

Elena Fedorova ◽

Janos Gyorgyey ◽

Attila Feher ◽

Spencer Brown ◽

...

Keyword(s):

Cell Cycle ◽

Medicago Sativa ◽

Retinoblastoma Protein ◽

Cyclin Dependent Kinase

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Tumor-suppressor p53 and the cell cycle

Current Opinion in Genetics & Development ◽

10.1016/s0959-437x(05)80340-5 ◽

1993 ◽

Vol 3 (1) ◽

pp. 50-54 ◽

Cited By ~ 70

Author(s):

Mary Ellen Perry ◽

Arnold J. Levine

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Tumor Suppressor P53

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Role of the p16 tumor suppressor gene in cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.3.1197 ◽

1998 ◽

Vol 16 (3) ◽

pp. 1197-1206 ◽

Cited By ~ 399

Author(s):

W H Liggett ◽

D Sidransky

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Human Cancer ◽

Suppressor Gene ◽

Premalignant Lesions ◽

Early Event ◽

Cyclin Dependent Kinase ◽

Primary Tumors

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.

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