A brain-specific activator of cyclin-dependent kinase 5

Lew, John I.; Huang, Qi; Zhong, Qi; Winkfein, Robert J.; Aebersold, Ruedi; Hunt, Tim; Wang, Jerry H.

doi:10.1038/371423a0

Cited by 559 publications

(513 citation statements)

References 23 publications

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“…The CDKAL1 has a domain similar to CDK5 regulatory subunit-associated protein 1 (CDK5RAP1), a neuronal protein that specifically inhibits activation of CDK5. 15 The reduced expression of CDKAL1 enhances activity of CDK5 in b cells and thus decreases insulin secretion. 16 The function of the CDKAL1 on insulin secretion would be influenced by alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

et al. 2011

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We examined the genetic associations of previously identified sequence variants with type 2 diabetes mellitus (T2DM) and its potentially genetic heterogeneity by gender in a large-scale cohort. A total of 613 T2DM patients and 8221 control subjects from the Korea Association REsource (KARE) cohort were included in the analysis of genetic association of T2DM with 33 nucleotide polymorphic markers identified by previous studies. The association analysis was further conducted with data partitioned by gender. The association analysis resulted in five nucleotide sequence variants associated with the susceptibility of T2DM after Bonferonni correction (Po0.0015). One was located near the gene of hematopoietically expressed homeobox (HHEX), and the others were all in the gene of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1). Further analysis revealed that the sequence variant (rs5015480) near HHEX and two SNPs (rs7756992 and rs9465871) in CDKAL1 were associated with the susceptibility of T2DM in females (Po0.005), but not in males (P40.005). We suggested heterogeneous genetic associations of the T2DM susceptibility with the CDKAL1 and HHEX genes by gender.

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Section: Discussionmentioning

confidence: 99%

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

et al. 2011

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“…In contrast, CDK9, whose expression is ubiquitous , shows an increased kinase activity in terminally di erentiated tissues (Bagella et al, 1998). This is similar to the CDK5 kinase, whose expression also appears not to be cell cycle dependent, and is higher in di erentiated tissues (Lew et al, 1994;Tsai et al, 1994). Because B-Myb is involved in mutually antagonistic interactions with factors associated with cell di erentiation and gene transcription, such as the retinoblastoma family member p107 (Sala et al, 1996b;Raschella' et al, 1997), we asked whether CDK9 could interfere with B-Myb activity.…”

Section: Introductionmentioning

confidence: 90%

Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene autoregulation

et al. 2000

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B-Myb is a transcription factor belonging to the myb family, whose activity has been associated with augmented DNA synthesis and cell cycle progression. We showed recently that B-Myb autoregulates its own expression through promoter transactivation. We report in this study that CDK9, the cyclin T associated kinase, which phosphorylates and activates RNA-Polymerase II, suppresses B-Myb autoregulation through direct interaction with the carboxyl-terminus of the B-Myb protein. Downregulation of the transactivating ability of B-Myb is independent of the kinase activity of CDK9, because a kinase de®cient mutant (dn-CDK9) also represses B-myb gene autoregulation. Overexpression of CDK9 did not result in suppression of p53-dependent transactivation or inhibition of the basal activity of the promoters tested so far, demonstrating that CDK9 is a B-Myb-speci®c repressor. Rather, transfection of the dominant negative dn-CDK9 construct inhibited the basal activity of the reporter genes, con®rming an essential role for CDK9 in gene transcription. In addition, Cyclin T1 restores B-Myb transactivating activity when co-transfected along with CDK9, suggesting that the down-regulatory e ect observed on B-Myb is speci®cally due to CDK9 alone. Thus, our data suggest that CDK9 is involved in the negative regulation of activated transcription mediated by certain transcription factors, such as B-Myb. This may indicate the existence of a feedback loop, mediated by the di erent activities of CDK9, which links basal with activated transcription.

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“…Only one CDK appears to be involved in cell cycle regulation in budding and ®ssion yeast (Elledge, 1996) while diverged, multiple members exist in higher eukaryotes. In higher eukaryotes, the di erent members play distinct functions in certain points of the cell cycle (reviewed by Sherr, 1993;Pines, 1995), and additional role in postmitotic neurons has been demonstrated for CDK5 (Tsai et al, 1994;Lew et al, 1994), and have also been suggested for other CDKs (Freeman et al, 1994). Similarly, only one member of the NIMA family probably exists in Aspergillus (Osmani and Ye, 1996), while mammals have at least six NIMA-related genes (Letwin et al, 1992;Schultz et al, 1994;Lu and Hunter, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…The activity of the CDKs is regulated at the di erent stages of the cell-cycle through reversible phosphorylation, and by binding of the CDKs to di erent cyclins, activators and inhibitors (Tsai et al, 1994;Lew et al, 1994;Morgan, 1995;Pines, 1995;Sherr and Roberts, 1995). The onset of mitosis is controlled by p34 cdc2 (CDK1), which form with its regulator, a B-type cyclin, a complex known as maturation, or mitosis promoting factor (MPF) (Nurse and Bissett, 1981;Lohka et al, 1988;Gautier et al, 1988;Arion et al, 1988;Simanis and Nurse, 1986;Minshull et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Murine NIMA-related kinases are expressed in patterns suggesting distinct functions in gametogenesis and a role in the nervous system

et al. 1998

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NIMA protein kinase is a major regulator of progression into mitosis in Aspergillus nidulans. Dominant negative forms of NIMA protein prevent entrance into mitosis in HeLa cells, suggesting that mammals have a similar pathway. We have reported previously the isolation of a murine NIMA-related kinase, designated Nek1, and more recently several additional NIMA-related human kinases have been cloned. The existence of several mammalian NIMA-related genes raises the questions of whether the di erent mammalian members have redundant, overlapping or distinct functions, and whether these functions are related to the role of NIMA in controlling mitosis. To address these questions we have studied the expression patterns of the di erent murine nek genes. To this end, we isolated a murine nek2 cDNA and compared its patterns of expression, during both gametogenesis and embryogenesis, to those of nek1. Both genes were highly expressed in developing germ cells, albeit in distinct patterns. In both females and males, nek1 is expressed much earlier than nek2, suggesting only limited ability for functional redundancy. Surprisingly, a striking speci®city of nek1 expression was found: high levels of nek1 RNA were observed in distinct regions of the nervous system, most notably in neurons of the peripheral ganglia. These patterns suggest that the di erent mammalian NIMA-related kinases participate in di erent phases of the meiotic process and may also have functions other than cell cycle control.

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A brain-specific activator of cyclin-dependent kinase 5

Cited by 559 publications

References 23 publications

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene autoregulation

Murine NIMA-related kinases are expressed in patterns suggesting distinct functions in gametogenesis and a role in the nervous system

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