Cyclin-dependent kinase-2 in the birth and death of cardiac muscle cells.

Abstract

The proliferative cell cycle in both vertebrates and much simpler organisms entails the transduction of mitogenic signals to cyclically expressed proteins known as cyclins and, hence, to their catalytically active targets, the cyclin-dependent protein kinases (cdks).1 2 In yeast, a single kinase, cdc28, suffices to partner with all of the cyclins, which are expressed sequentially in the G1 (cln 1/2/3), S (clb 5/6), and G2/M phases of the cycle, respectively. In mammals, by contrast, D-type cyclins in G1 partner with cdk4/6, cyclins E and A sequentially partner with cdk2 in S phase, and cyclin B interacts with cdc2 for entry into M phase. Whereas one family of cdk inhibitors is specific for cdk4/6 (the INK4 family, comprising p15, p16, p18, and p19), a second, the Cip/Kip family, has much broader activity, inhibiting cdk2 and cdc2 in addition. Activation of the cell cycle through induction of cyclin D occurs in large part by the titration of Cip/Kip proteins away from cdk2 to the cyclin D–cdk complexes. Substrates of primary importance to the actions of cdk4/6 are the retinoblastoma family of pocket proteins, whereas much less is known about the substrates for cdk2, although some have been identified.3 One source of positive feedback within this process is that phosphorylation by cdc28 and cdk2 can promote the degradation of cdk inhibitors using the ubiquitin-proteasome pathway. A second source is that cdk2, whose enzymatic activation thus depends on cdk4/6, also phosphorylates pocket proteins in sequential or processive fashion. In addition, the mitogen-induced transcription factor Myc likewise causes S-phase entry by activating cdk2 in parallel with the pocket protein pathway.4 Thus, together these positive and negative regulators form a complex and interdependent network tightly regulating the cell cycle, in which the kinase activity of …