Cyclin-dependent kinases regulate apoptosis of intestinal epithelial cells

Sujoy Bhattacharya, Ramesh M. Ray, Leonard R. Johnson

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Homeostasis of the gastrointestinal epithelium is dependent upon a balance between cell proliferation and apoptosis. Cyclin-dependent kinases (Cdks) are well known for their role in cell proliferation. Previous studies from our group have shown that polyamine-depletion of intestinal epithelial cells (IEC-6) decreases cyclin-dependent kinase 2 (Cdk2) activity, increases p53 and p21Cip1 protein levels, induces G1 arrest, and protects cells from camptothecin (CPT)-induced apoptosis. Although emerging evidence suggests that members of the Cdk family are involved in the regulation of apoptosis, their roles directing apoptosis of IEC-6 cells are not known. In this study, we report that inhibition of Cdk1, 2, and 9 (with the broad range Cdk inhibitor, AZD5438) in proliferating IEC-6 cells triggered DNA damage, activated p53 signaling, inhibited proliferation, and induced apoptosis. By contrast, inhibition of Cdk2 (with NU6140) increased p53 protein and activity, inhibited proliferation, but had no effect on apoptosis. Notably, AZD5438 sensitized, whereas, NU6140 rescued proliferating IEC-6 cells from CPT-induced apoptosis. However, in colon carcinoma (Caco-2) cells with mutant p53, treatment with either AZD5438 or NU6140 blocked proliferation, albeit more robustly with AZD5438. Both Cdk inhibitors induced apoptosis in Caco-2 cells in a p53-independent manner. In serum starved quiescent IEC-6 cells, both AZD5438 and NU6140 decreased TNF-α/CPT-induced activation of p53 and, consequently, rescued cells from apoptosis, indicating that sustained Cdk activity is required for apoptosis of quiescent cells. Furthermore, AZD5438 partially reversed the protective effect of polyamine depletion whereas NU6140 had no effect. Together, these results demonstrate that Cdks possess opposing roles in the control of apoptosis in quiescent and proliferating cells. In addition, Cdk inhibitors uncouple proliferation from apoptosis in a p53-dependent manner.

Original languageEnglish (US)
Pages (from-to)451-466
Number of pages16
JournalApoptosis
Volume19
Issue number3
DOIs
StatePublished - Mar 1 2014

Fingerprint

Cyclin-Dependent Kinases
Epithelial Cells
Apoptosis
Camptothecin
Cyclin-Dependent Kinase 2
Caco-2 Cells
Cell proliferation
Polyamines
Cell Proliferation
DNA Damage
AZD5438
Colon
Proteins
Homeostasis
Epithelium
Chemical activation
4-(6-cyclohexylmethoxy-9H-purin-2-ylamino)-N,N-diethylbenzamide

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

Cite this

Cyclin-dependent kinases regulate apoptosis of intestinal epithelial cells. / Bhattacharya, Sujoy; Ray, Ramesh M.; Johnson, Leonard R.

In: Apoptosis, Vol. 19, No. 3, 01.03.2014, p. 451-466.

Research output: Contribution to journalArticle

Bhattacharya, Sujoy ; Ray, Ramesh M. ; Johnson, Leonard R. / Cyclin-dependent kinases regulate apoptosis of intestinal epithelial cells. In: Apoptosis. 2014 ; Vol. 19, No. 3. pp. 451-466.
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