Cyclin-Dependent Kinase 5 Is Associated with Apoptotic Cell Death during Development and Tissue Remodeling

Abstract

In a series of studies to more precisely localize the cellular sites of expression of the cyclin-dependent kinase (Cdk) family members in reproductive organs, we observed a striking expression of Cdk5 in atretic follicles in the ovary, particularly in granulosa cells that appeared to be dying. We determined that these granulosa cells were undergoing apoptotic cell death using the in situ DNA fragmentation assay. To extend the generality of the association of Cdk5 with apoptotic cells, we examined its expression as it correlated with the detection of apoptosis in a number of developmental paradigms, including regions of the embryonic nervous system, the developing eye, and the developing limb. Finally, the association of apoptosis and Cdk5 expression and associated kinase activity was examined in the limb and in an induced cell death system, that of androgen withdrawal-induced regression of the prostate gland in male mice. These observations provide new insight into the possible function of this novel Cdk during both differentiation and apoptotic cell death.

hob1+, the fission yeast homolog of Bin1, is dispensable for endocytosis or actin organization, but required for the response to starvation or genotoxic stress

“…Although a PHO85 homolog has not been described in fission yeast to date, its action might be relevant to the stress-related processes implied here for hob1+. In support of this possibility, Bin1 can be phosphorylated by the cell cycle-related kinase Cdk5 (A -X Liu, J DuHadaway, and GCP, unpublished observations), which is reported to be the Pho85p homolog in mammals (Huang et al, 1999) that functions in stress and apoptotic signaling in certain settings Yin et al, 1999;Zhang et al, 1997;Patrick et al, 1999;Gao et al, 2001). Although speculative, connections to a cell cycle/stress-related kinase such as Pho85p would support the conclusion that hob1+ is a signal transducer that integrates stress signals with cell cycle control at some level.…”

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

“…Cdk5 kinase activity was assayed as described by Zhang et al 5 Equal amounts of lysates from different cell samples were incubated with 1.5 mg/ ml Cdk5 antibody for 1 h at 41C, and then purified by the addition of protein A-Sepharose (Boehringer Mannheim, Germany). The precipitated beads were equilibrated in kinase buffer (50 mM Tris, pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 20 mM EGTA, 0.1 mM sodium vanadate, 80 mM bglycerophosphate) and collected by centrifugation.…”

“…1 Cdk5 is expressed at both mRNA and protein levels in a broad spectrum of tissues and cell lines, with the highest levels detected in neurons. [2][3][4][5][6] Unlike other cell cycle-promoting members of Cdk family, Cdk5 kinase primarily modulates neuroskeletal dynamics in postmitotic neurons. 3,7,8 Cdk5 plays an essential role in both developing and adult neurons, including neuronal migration, 9,10 axon guidance, 11 neurite outgrowth, 7 dynamics of synaptic structure, [12][13][14] neurotransmission, 15,16 and neuronal secretion.…”

“…It is also prominent in the testis, where its level is high but its function is unknown (our unpublished data), developing muscle, 19,20 bFGF-stimulated bovine aortic endothelial cell proliferation, 21 and differentiating monocytes. 22,23 Cdk5 is activated in dying cells, including both developing tissues (interdigital areas of mouse limbs, 24 differentiating rat lens, 4 and mouse brain 5 ) and adult tissues (regressing mouse prostate following androgen withdrawal and atrophic mouse ovaries 5 ). The association between Cdk5 activation and cell death is seen in pathology: rat lungs infected with Streptococcus pneumoniae, 25 mouse limbs infected with Leishmania major, 26 preterm lamb lungs after ventilation, 27 cyclophosphamide-treated mouse embryos, 28 and several neurodisorders and neuronal injuries.…”

Accumulation of high levels of the p53 and p130 growth-suppressing proteins in cell lines stably over-expressing cyclin-dependent kinase 6 (cdk6)

“…Recent data (Hofmann and Livingston, 1996;Hengstschlager et al, 1999) suggest that it plays a role in activation of certain members of the E2F family of transcription factors, which are essential for the G1 to S transition in cells. Some cdks, such as cdk5 and perhaps cdk9, may not even play a direct role in cell cycle progression itself, but rather may serve a function in di erentiation and/or apoptosis, at least in certain cell types (Tang and Wang, 1996;Zhang et al, 1997;Bagella et al, 1998;MacLachlan et al, 1998). Other cdks, such as cdks7, 8 and 9, appear to be involved in regulation of activity of RNA polymerase II (Feaver et al, 1994;Rickert et al, 1996;Edwards et al, 1998;Fujinaga et al, 1998;Wei et al, 1998).…”