Differential regulation of gene expression by protein kinase C isozymes as determined by genome-wide expression analysis.
Protein kinase C (PKC) isozymes are key signal transducers involved in normal physiology and disease and have been widely implicated in cancer progression. Despite our extensive knowledge of the signaling pathways regulated by PKC isozymes and their effectors, there is essentially no information on how individual members of the PKC family regulate gene transcription. Here, we report the first PKC isozyme-specific analysis of global gene expression by microarray using RNAi depletion of diacylglycerol/phorbol ester-regulated PKCs. A thorough analysis of this microarray data revealed unique patterns of gene expression controlled by PKCα, PKCδ, and PKCε, which are remarkably different in cells growing in serum or in response to phorbol ester stimulation. PKCδ is the most relevant isoform in controlling the induction of genes by phorbol ester stimulation, whereas PKCε predominantly regulates gene expression in serum. We also established that two PKCδ-regulated genes, FOSL1 and BCL2A1, mediate the apoptotic effect of phorbol esters or the chemotherapeutic agent etoposide in prostate cancer cells. Our studies offer a unique opportunity for establishing novel transcriptional effectors for PKC isozymes and may have significant functional and therapeutic implications.
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
M Cecilia
MC
Caino
Vivian A
VA
von Burstin
Cynthia
C
Lopez-Haber
Marcelo G
MG
Kazanietz
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D005047:Etoposide / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D055106:Genome-Wide Association Study; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D007527:Isoenzymes; D010703:Phorbol Esters; D005047:Etoposide; D011493:Protein Kinase C
Mol Cell Biol. 2002 Jan;22(1):182-95
11739733
Mol Endocrinol. 2002 Dec;16(12):2840-52
12456804
J Biol Chem. 2010 Aug 20;285(34):26033-40
20566643
Cell Death Differ. 2005 Sep;12(9):1225-39
16094403
EMBO J. 2007 Apr 4;26(7):1878-90
17347653
Cell. 1987 Jun 19;49(6):741-52
3034433
Am J Respir Cell Mol Biol. 2000 Feb;22(2):150-6
10657935
Eur Respir J. 2009 Nov;34(5):1171-9
19324950
J Biol Chem. 1996 Oct 18;271(42):26074-80
8824249
Eur Respir J. 2008 Apr;31(4):725-35
18184679
Oncogene. 1990 Mar;5(3):427-31
2107494
Biochem J. 2003 Jun 15;372(Pt 3):787-97
12628005
Am J Physiol Lung Cell Mol Physiol. 2000 Sep;279(3):L429-38
10956616
Nat Rev Cancer. 2007 Apr;7(4):281-94
17384583
Nature. 1987 Oct 15-21;329(6140):648-51
2821407
Cancer Res. 2008 Jul 15;68(14):5648-57
18632617
J Neurosurg. 2009 Aug;111(2):211-8
19301967
Cell Death Differ. 2006 Dec;13(12):2150-3
16710367
Oncogene. 2003 Sep 11;22(39):7958-68
12970744
Oncogene. 1998 Sep 10;17(10):1223-34
9771965
J Biol Chem. 2000 Mar 17;275(11):7574-82
10713064
Curr Pharm Des. 2001 Nov;7(17):1725-44
11562308
Bioinformatics. 2003 Feb 12;19(3):368-75
12584122
Am J Pathol. 1999 Jan;154(1):137-44
9916928
Int J Cancer. 2006 Mar 15;118(6):1572-6
16184549
Mol Pharmacol. 2010 Sep;78(3):325-32
20516369
Cancer Res. 2002 Apr 15;62(8):2423-9
11956106
J Biol Chem. 2005 Nov 25;280(47):38982-91
16183650
J Clin Invest. 2002 Mar;109(6):827-36
11901191
Blood. 2005 Dec 1;106(12):3955-7
16099884
Cancer Res. 1995 Nov 1;55(21):4844-9
7585518
J Biol Chem. 1996 Oct 25;271(43):27025-30
8900191
J Biol Chem. 1993 Mar 25;268(9):6090-6
8454583
J Biol Chem. 2001 Mar 16;276(11):8087-93
11098060
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
16199517
Free Radic Biol Med. 2008 Apr 15;44(8):1656-67
18291120
J Immunol. 2006 Nov 15;177(10):7193-202
17082637
Int J Mol Med. 2002 Nov;10(5):541-5
12373288
Oncogene. 2006 May 25;25(22):3123-38
16434969
J Cell Sci. 2004 Jan 15;117(Pt 2):131-2
14676268
Cell Signal. 2007 Aug;19(8):1633-42
17537614
J Biol Chem. 2006 Apr 7;281(14):9728-37
16452485
J Biol Chem. 1995 Jan 6;270(1):78-86
7814423
Mol Cell Biol. 1998 Feb;18(2):790-8
9447975
Mol Cell Biol. 2005 Aug;25(15):6454-63
16024783
J Biol Chem. 1999 Jul 2;274(27):19115-23
10383415
Leuk Res. 2005 Aug;29(8):923-31
15978943
Cancer Res. 2007 Jul 1;67(13):6204-11
17616677
Oncogene. 2005 Feb 17;24(8):1434-44
15608675