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Ana M. Gamero, PhD

Assistant Professor, Biochemistry

Assistant Professor, Fels Institute for Cancer Research and Molecular Biology

Telephone:  215-707-1268

Fax:  215-707-7536

Email: gameroa@temple.edu

Department of Biochemistry

Fels Institute for Cancer Research and Molecular Biology

BS, University of South Florida, Tampa, FL, 1990

 

PhD, University of South Florida, Tampa, FL, 1996

 

Postdoctoral fellowship, Cleveland Clinic Foundation, Cleveland, OH, 1997

 

National Cancer Institute (NCI) Scholar, NCI, Frederick, MD, 2003

 

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Research in my laboratory is focused on uncovering the molecular mechanism of type I IFN α/ß-induced apoptosis. We aim to define how the transcription factor, STAT2, shapes the decision making process to apoptosis and its role in cancer. Type I IFNs are a family of cytokines with multiple biological effects. They are approved drugs for the adjuvant treatment of certain malignancies and clinical trials have shown that IFN-α therapy prolongs patient survival, but only in a subset of patients. However, it is not clear how IFNs choose to disrupt tumor growth. For instance, the antitumor effects of IFN α/ß are unpredictable as IFN treatment of tumor cells can lead to either inhibition of cell growth or alternatively activation of apoptosis.

Type I IFNs induce the activation of the transcription factors: STAT1 and STAT2, which enter the nucleus assembled as STAT1 homodimers and/or STAT1/2 heterodimers in association with IFN regulatory factor (IRF)-9 collectively called ISGF3. STAT complexes bind to specific DNA elements found in the promoters of IFN inducible genes. While STAT1 homodimers bind to the gamma activation sequence (GAS), the ISGF3 complex binds to the interferon stimulated response element (ISRE) that together activate the expression of multiple genes that in turn mediate the biological activities of type I IFNs.

Work from my laboratory has accumulated evidence to define STAT2 as a critical component in mediating type I IFN-induced apoptosis. Using tumor cells that are susceptible to the apoptotic effects of IFN-α, we have made several observations. A loss of STAT2 impairs the activation of the mitochondrial-dependent death pathway and gene activation. We identified a conserved structural motif termed “PYTK” in the SH2 domain of STATs that when mutated in STAT2 alters the apoptotic effects of IFN-α. Our studies also revealed the lesser contribution of STAT1 homodimers in the induction of apoptosis by type I IFNs. In fact, a deficiency in STAT2 neither affects the activation of STAT1 nor the expression of STAT1 regulated genes.

What remains undiscovered is:

1. How STAT2 transmits apoptotic signals to cells destined to be killed
2. Whether STAT2 interacts with other proteins to promote apoptosis
3. The identification of a subset of STAT2 regulated apoptotic genes
4. Whether STAT2 is important in cancer prevention or tumor progression
5. The existence of spontaneous STAT2 mutations in the tumors of patients
   

These questions are active areas of investigation in my laboratory. From a clinical perspective, we wish to determine whether defects in STAT2 function may be associated with less than optimal antitumor clinical responses seen with IFN-α therapy. Hence, understanding the death signaling mechanism mediated by STAT2 will yield important information for better clinical application of IFNs as this transcription factor may be deemed a molecular cancer biomarker.

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• International Society for Interferon and Cytokine Research (ISICR)
• American Association for the Advancement of Science (AAAS)

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Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

18698163. Maher SG, Sheikh F, Scarzello AJ, Romero-Weaver AL, Baker DP, Donnelly RP, Gamero AM, IFNalpha and IFNlambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity. Cancer Biol Ther 7:7(1109-15)2008 Jul

17504213. Maher SG, Romero-Weaver AL, Scarzello AJ, Gamero AM, Interferon: cellular executioner or white knight? Curr Med Chem 14:12(1279-89)2007

17442890. Scarzello AJ, Romero-Weaver AL, Maher SG, Veenstra TD, Zhou M, Qin A, Donnelly RP, Sheikh F, Gamero AM, A Mutation in the SH2 domain of STAT2 prolongs tyrosine phosphorylation of STAT1 and promotes type I IFN-induced apoptosis. Mol Biol Cell 18:7(2455-62)2007 Jul

16601124. Gamero AM, Potla R, Wegrzyn J, Szelag M, Edling AE, Shimoda K, Link DC, Dulak J, Baker DP, Tanabe Y, Grayson JM, Larner AC, Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-beta in primary pro-B cells. J Biol Chem 281:24(16238-44)2006 Jun 16

16413919. Gamero AM, Oppenheim JJ, IL-1 can act as number one. Immunity 24:1(16-7)2006 Jan

16337360. Gamero AM, Potla R, Sakamoto S, Baker DP, Abraham R, Larner AC, Type I interferons activate apoptosis in a Jurkat cell variant by caspase-dependent and independent mechanisms. Cell Signal 18:8(1299-308)2006 Aug

15879595. Kim HP, Korn LL, Gamero AM, Leonard WJ, Calcium-dependent activation of interleukin-21 gene expression in T cells. J Biol Chem 280:26(25291-7)2005 Jul 1

14998485. Gamero AM, Young HA, Wiltrout RH, Inactivation of Stat3 in tumor cells: releasing a brake on immune responses against cancer? Cancer Cell 5:2(111-2)2004 Feb

14769148. Navarro A, Frevel M, Gamero AM, Williams BR, Feldman G, Larner AC, Thrombomodulin RNA is destabilized through its 3'-untranslated element in cells exposed to IFN-gamma. J Interferon Cytokine Res 23:12(723-8)2003 Dec

14722125. Gamero AM, Sakamoto S, Montenegro J, Larner AC, Identification of a novel conserved motif in the STAT family that is required for tyrosine phosphorylation. J Biol Chem 279:13(12379-85)2004 Mar 26

12096086. Bauer JA, Morrison BH, Grane RW, Jacobs BS, Dabney S, Gamero AM, Carnevale KA, Smith DJ, Drazba J, Seetharam B, Lindner DJ, Effects of interferon beta on transcobalamin II-receptor expression and antitumor activity of nitrosylcobalamin. J Natl Cancer Inst 94:13(1010-9)2002 Jul 3

11278370. Gamero AM, Larner AC, Vanadate facilitates interferon alpha-mediated apoptosis that is dependent on the Jak/Stat pathway. J Biol Chem 276:17(13547-53)2001 Apr 27

10748192. Gamero AM, Larner AC, Signaling via the T cell antigen receptor induces phosphorylation of Stat1 on serine 727. J Biol Chem 275:22(16574-8)2000 Jun 2

9926943. Liu JH, Wei S, Burnette PK, Gamero AM, Hutton M, Djeu JY, Functional association of TGF-beta receptor II with cyclin B. Oncogene 18:1(269-75)1999 Jan 7

9607917. Wei S, Gamero AM, Liu JH, Daulton AA, Valkov NI, Trapani JA, Larner AC, Weber MJ, Djeu JY, Control of lytic function by mitogen-activated protein kinase/extracellular regulatory kinase 2 (ERK2) in a human natural killer cell line: identification of perforin and granzyme B mobilization by functional ERK2. J Exp Med 187:11(1753-65)1998 Jun 1

8943427. Wei S, Liu JH, Epling-Burnette PK, Gamero AM, Ussery D, Pearson EW, Elkabani ME, Diaz JI, Djeu JY, Critical role of Lyn kinase in inhibition of neutrophil apoptosis by granulocyte-macrophage colony-stimulating factor. J Immunol 157:11(5155-62)1996 Dec 1

7585540. Gamero AM, Ussery D, Reintgen DS, Puleo CA, Djeu JY, Interleukin 15 induction of lymphokine-activated killer cell function against autologous tumor cells in melanoma patient lymphocytes by a CD18-dependent, perforin-related mechanism. Cancer Res 55:21(4988-94)1995 Nov 1

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