Cyclin half-life

Cyclins D and E in mammals are short-hved proteins with a lifetime of only ca. 20 min. Their instability is due to the occurrence of certain sequences in the C-terminal region deletion of these sequences is associated with stabilization of the cyclins (see 13.3.1). These sequence elements are known as PEST sequences, based on their composition. Due to the short half-life, the D type cyclins require a constant stimulus at the transcription level to achieve the concentration in Gi phase necessary for activation of CDK4/6 and to initiate crossing of the restriction point. 

The growth factor-dependent synthesis of D-type cyclins occurs during the Go/Gi transition and peak in concentration in late Gi phase (13). These proteins have a very short half-life and are degraded rapidly after removal of mitogenic stimulation. The INK family of CKIs primarily inhibits cyclin D/CDK4/6 complexes. Only when the concentration of cyclin D exceeds that of the INK proteins can these cyclin D/CDK4/6 complexes overcome their inhibition (14, 15). 

Cyclodextrin complexation (See Chapter 40) can also represent a way to improve the stability and the solubility of sensitive drugs such as thalidomide. Thalidomide is currently in clinical use for the treatment and prevention of graft-versus-host disease in leukemia patients after bone marrow transplant. However, this drug is sparingly soluble in aqueous solutions (50 Kig/mL) and is readily hydrolyzed. Complexation with hydroxypropyl (3-cyclodextrin increases the solubility to 1700 Kig/mL and extends the half-life of a dilute solution from 2.1 to 4.1 h. Other vulnerable and sparingly soluble drugs stabilized by means of cyclodextrin complexation are the non-steroidal antiinflammatory drugs diclofenac, piroxicam, and indomethacin and the anthra-cycline antibiotic daunorubicin. ... 

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