The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons.

Lee, Mong Hong; Nikolic, Margareta; Baptista, Carlos; Lai, Eseng; Tsai, Li Huei; Massagué, Joan

doi:10.1073/pnas.93.8.3259

Cited by 115 publications

(96 citation statements)

References 34 publications

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“…Moreover, overexpression of p27 kip1 alone is sufficient to induce neuronal differentiation in a mouse neuroblastoma cell line (52). The kinase activity of p35⅐Cdk5, however, is not inhibited by p21 cip1/WAF1 or p27 kip1 (33,34). We also found that the activity of bacterially expressed p25⅐Cdk5 is not inhibited by recombinant p21 cip1/WAF1 or p27 kip1 .…”

Section: Discussionsupporting

confidence: 50%

Identification of Functional Domains in the Neuronal Cdk5 Activator Protein

Poon

Lew

Hunter

1997

Journal of Biological Chemistry

103

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Cyclin-dependent kinase 5 (Cdk5) is activated by the neuronal-specific activator protein, p35. In contrast to the activation of typical CDKs by cyclin subunits, p35⅐Cdk5 was not further activated by the CDK-activating kinase (CAK) and was neither phosphorylated nor inhibited by the Tyr-15-specific Wee1 kinase. The previously identified proteolytic active fragment of p35, p25 (residues 91-307) as well as the slightly smaller fragment containing residues 109 -291, was found to be sufficient to bind and activate Cdk5. Other CDKs, including Cdk2, associated weakly with p25. However, their kinase activity was only activated to the low level observed for cyclin A⅐Cdk2 without Thr-160 phosphorylation, and phosphorylation of Thr-160 in Cdk2 did not activate the p25⅐Cdk2 complex further. We have identified distinct regions in p35 required for binding to Cdk5 or activation of Cdk5. Residues ϳ150 -200 of p35 were sufficient for binding to Cdk5, but residues ϳ279 -291 were needed in addition for activation of Cdk5 in vitro.Cyclins and cyclin-dependent kinases (CDKs) 1 are key regulators of the eukaryotic cell cycle (1). Cdc2 is associated with B-type cyclins and regulates M phase (2). Cdk2 is associated with A-and E-type cyclins, and the respective complexes are believed to control the S phase and G 1 -S transition, respectively (3, 4). Cdk4 and Cdk6 are associated with the D-type cyclins and are important for G 1 progression (3).The activity of CDKs is tightly regulated by an intricate system of protein-protein interaction and phosphorylation (5). The activation of CDKs, by definition, requires the association with cyclin partners. Full activation of CDKs requires in addition the phosphorylation of Thr-161/Thr-160, which lies in the activating T-loop in the crystal structure of Cdk2 (6, 7). The Thr-161/Thr-160 residue is phosphorylated by the CDK-activating kinase (CAK), which is composed of a cyclin H-Cdk7 complex and a RING finger protein subunit MAT1 (8). The activity of CDKs can be inhibited by phosphorylation of Thr-14 and Tyr-15 by the Wee1 and Myt1 protein kinases (9). Furthermore, CDKs can be inactivated by binding to CDK inhibitors like those from the p21 cip1/WAF1 family (p21 cip1/WAF1 , p27 kip1 , and p57 kip2 ) and the p16 INK4A family (p16 INK4A , p15 INK4B

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Section: Discussionsupporting

confidence: 50%

Identification of Functional Domains in the Neuronal Cdk5 Activator Protein

Poon

Lew

Hunter

1997

Journal of Biological Chemistry

103

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“…One possibility is that association of cyclin D2 with cdk-5 enables the Cip/Kip family of cdk inhibitors (for reviews, see Lees, 1995;Pines, 1995;Sherr and Roberts, 1995) to bind to cdk-5 and abolish cdk-5 activity, whereas association of p35 with cdk-5 is refractory to Cip/Kip binding. Indeed, it has recently been demonstrated that one Cip/Kip inhibitor that is highly expressed in postmitotic neurones, p27 KipI binds in vitro to cdk-5/cyclin D2 complexes but not to cdk-5/p35 complexes (Lee et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Cyclin D2 Interacts with cdk‐5 and Modulates Cellular cdk‐5/p35 Activity

Guidato

McLoughlin

Grierson

et al. 1998

Journal of Neurochemistry

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Cyclin-dependent kinase-5 (cdk-5) is a serine! threonine kinase that displays neurone-specific activity. Experimental manipulation of cdk-5 expression in neurones has shown that cdk-5 is essential for proper development of the nervous system and, in particular, for outgrowth of neurites. Such observations suggest that cdk-5 activity must be tightly controlled during development of the nervous system. To identify possible regulators of cdk-5, we used the yeast two-hybrid system to search for proteins that interact with cdk-5. In two independent yeast transformation events, cyclin D2 interacted with cdk-5. Immunoprecipitation experiments confirmed that cyclin D2 and cdk-5 interact in mammalian cells. Cyclin D2 did not activate cdk-5 as assayed using three different substrates, which was in contrast to a known cdk-5 activator, p35. However, cyclin D2 expression led to a decrease in cdk-5/p35 activity in transfected cells. As cyclin D2 and cdk-5 are known to share overlapping patterns of expression during development of the CNS, the results presented here suggest a role for cyclin D2 in modulating cdk-5 activity in postmitotic developing neurones. Key Words: Cyclin-dependent kinase-5 -p35-Cyclin D2 -Neurofilaments-Tau.

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“…Recent works offer insights into the molecular mechanisms by which ATRA exerts its biological effects on neuroblastomas. All-trans-retinoic acid activates phosphatidylinositol 3 0 -kinase-Akt pathway that plays an important role in neuronal differentiation (Encinas et al, 1999;Lopez-Carballo et al, 2002), and it reduces the expression levels of MYCN (Thiele et al, 1985) and upregulates the cyclin-dependent kinase (CDK) inhibitor p27 KIP1 in association with the ATRA-induced cell cycle arrest in neuroblastoma cells (Lee et al, 1996;Nakamura et al, 2003). In addition, certain neuroblastoma cells underwent apoptosis in response to ATRA (Piacentini et al, 1992;Takada et al, 2001;Nagai et al, 2004).…”

Section: Introductionmentioning

confidence: 99%