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Xavier Grana, PhDXavier Grana, PhD

 

Associate Professor, Biochemistry

Associate Professor, Fels Institute for Cancer Research and Molecular Biology

Director, Molecular Biology and Genetics Graduate Program

Telephone:  215-707-7416

Fax:  215-707-2805

Email: xavier@temple.edu

 

Department of Biochemistry

Fels Institute for Cancer Research and Molecular Biology

 

Educational Background:

 

BSc, Biology (5-year program), University of Barcelona, Spain, 1982-1985

 

PhD, Biology (Molecular Biology and Biochemistry). University of Barcelona, 1991

 

Postdoctoral Fulbright Fellow, Cold Spring Harbor, NY, 1991-1992


Postdoctoral Fulbright Fellow, Fels Institute for Cancer Research and Molecular Biology, Temple University, 1992-1993


Postdoctoral Lady Tata Memorial Fellow, Fels Institute for Cancer Research and Molecular Biology, Temple University, 1993-1994

 

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Research Interests:

 

Cell cycle control in mammalian cells and its deregulation in cancer. Role of cyclins, cyclin dependent kinases (CDKs), Ser/Thr protein phosphatases and tumor suppressor genes.

 

Research in my laboratory focuses on the molecular mechanisms that govern the cell cycle of normal and malignant eukaryotic cells, with a particular interest in the molecular signaling that controls cell cycle specific gene expression.  Our major focus is on the mechanisms that govern cell cycle entry and exit, which operate in the G1 phase of the cell cycle. When higher eukaryotic cells exit the cell cycle they have three different fates, terminal differentiation, senescence or quiescence.  While the first two fates are typically irreversible, quiescent cells can reenter the cell cycle when the environment is appropriate.  Eukaryotic cells have evolved to respond to a large array of growth promoting and inhibiting signals, which are eventually integrated by a conserved protein engine consisting of distinct cyclin/CDK (Cyclin Dependent Kinase) holoenzymes.  CDKs are activated at specific stages of the cell cycle and their activities are required for progression through S phase and mitosis (reviewed by Graña and Reddy, 1995; Graña et al., 1998, Sotillo and Graña, 2010).  I am interested in how these regulatory pathways are disrupted in cancer cells as well as in cells transformed by small DNA viruses or infected by HIV (Graña et al., 1998, Garriga and Graña, 2004, Sotillo and Graña, 2010).

 

Grana Figure 1

 

One initial focus of this laboratory was the characterization of p130, a protein structurally and functionally related to the product of the retinoblastoma susceptibility tumor suppressor gene (reviewed in Mayol and Graña, 1997; 1998; Graña et al., 1998).  We first identified phosphorylation as a major mechanism for regulation of p130 in G1 and G0 (Mayol et al., 1995; Mayol et al., 1996).  We, and others, found that p130 is phosphorylated during the cell cycle by the concerted action of D-type cyclin/CDKs and cyclin E/CDK2 holoenzymes (Parreño et al., 2001, Calbo et al., 2002), and determined mechanisms by which the E1A oncogene modulates pocket protein phosphorylation (Parreño et al., 2000 and Parreño et al., 2001). In addition, we and others reported on the relationship between the protein levels and phosphorylation status of pocket proteins (Mayol et al., 1996; Garriga et al., 1998a), eventually showing that p130 protein levels are regulated by the SCFSKP2 ubiquitin ligase (Bhattacharya et al., 2003).  Recently, our focus has expanded to studies dealing with the coordinated regulation of the three members of the retinoblastoma family of proteins by CDKs and Ser/Thr phosphatases in response to a variety of signals (Calbo et al., 2002 and Garriga et al., 2004).  In our efforts to better understand the G0/G1 transition we have found that certain serum starved tumor cells enter the cell cycle in the absence of mitogens following ectopic expression of G1 cyclins (Calbo et al., 2002). More recently we discovered that in quiescent normal human fibroblast, deregulation of cyclin E is not sufficient to induce cell cycle entry.  We have subsequently found that this is due to the inability of cyclin E to activate CDK2 in normal cells.  However, this can be bypassed by co-expressing SV-40 small t antigen (st), which cooperates with cyclin E to induce phosphorylation of CDK2 at its activating residue leading to CDK2 activation.  Cyclin E and st cooperate to bypass quiescence induced by multiple signals and endow cells with transformed characteristics (Sotillo et al. 2008).  We subsequently identified the essential replication factor CDC6 as a target of st, whose expression appears required for activation of CDK2 and cell cycle progression when the cell cycle is driven by the oncogenic expression of st and cyclin E (Sotillo et al. 2009, reviewed in Sotillo and Graña 2010).  Moreover, we are also interested in gaining a better understanding as to how Ser/Thr protein phosphatases reverse the action of CDKs during the cell cycle (Garriga et al., 2004), and have recently identified particular PP2A holoenzymes implicated in this process (Jayadeva et al, 2010), reviewed in Kurimchak and Graña (2012).

 

Grana fig. 2

 

The other primary area of research in this lab deals with the functional characterization of CDK9 (formerly named, PITALRE), cloned by means of its partial sequence identity to the CDC2 kinase (Graña et al., 1994; Garriga et al., 1996a and Garriga et al., 1996b).  Following the identification of CDK9 as a subunit of the Positive Transcription Elongation Factor b (P-TEFb) and HIV tat associated kinase (TAK) by Dr. David Price’s group (University of Iowa), we demonstrated that the levels of cyclin T1, one of the three cyclins that bind to and activate CDK9, is upregulated during T-cell activation.  Upregulation of cyclin T1 expression correlates with phosphorylation of RNA polymerase II (RNA pol II) in vivo and HIV-1 replication (Garriga et al., 1998b).  Subsequently, we have characterized the signaling pathways and mechanisms responsible for cyclin T1 upregulation during T cell activation (Marshall et al., 2005).  We have also found that in primary human T cells it is possible to directly inhibit CDK9 to levels that do not affect T cell activation, but potently inhibit HIV-1 replication (Salerno et al., 2007).  Moreover, we have found that, although CDK9/cyclin T1 complexes are targeted by the SCFskp2 ubiquitin ligase under certain conditions, this association does not seem to regulate CDK9 expression during the cell cycle (Garriga et al., 2003).  Current efforts in the laboratory are aimed at identifying CDK9 dependent genes (Garriga et al., 2010) and understanding their regulation in a variety of human cells (Keskin et al., 2012).

 

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CURRENT GRADUATE STUDENTS:

 

Graduate Students Present Position
Alison Kurimchak (Class of 2010) Molecular Biology and Genetics PhD student

 

 

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PREVIOUS GRADUATE STUDENTS:

Graduate Students Graduation Year Present Position

Renee Marshall

Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human PBLs.

PhD 2005

Mol. Biol. & Genetics

Postdoctoral Fellow, U. Penn

Sabyasachi Bhattacharya (MS student)

SKP2 associates with p130 and accelerates p130 ubiquitination and degradation in human cells.

MS 2003 Biochemistry

PhD student, TUSM

Currently Postdoctoral Fellow at U. Penn

Dominic Salerno

Differential effects on HIV replication and T cell activation following direct inhibition of CDK9 or flavopiridol treatment in PBLs

PhD 2007

Mol. Biol. & Genetics

Postdoctoral Fellow, TUSM

Girish Jayadeva

B55alpha-PP2A holoenzymes modulate the phosphorylation status of the pRB related p107 and p130 proteins

PhD 2009

Mol. Biol. & Genetics

Manager, BIOCON, India

Arun Jayaraman

Characterization of the p130/E2F-1 interaction

2008

MD/PhD

Resident, U. of Pittsburgh

Alison Kurimchak

Developing high throughput screening tools to identify small molecule inhibitors of HIV transcription

MS 2010

Mol. Biol. & Genetics

PhD student

 

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PREVIOUS POSTDOCTORAL AND OTHER FELLOWS:

Xavier Mayol, PhD

Postdoctoral Fellow

1994-1996

Principal Investigator
Univ. Pompeu Fabra, Spain

Judith Garriga, PhD

Postdoctoral Fellow

Associate Scientist

1994-1999

1999-2000

Adjunct Assistant Professor
Fels Institute, TUSM

Matilde Parreño, PhD

Postdoctoral Fellow

1996-2001

Principal Investigator, Hospital de Sant Pau, Barcelona, Spain

Ana Limón, PhD

Postdoctoral Fellow

1997-1999

Scientist, SRL and Massachusetts General Hospital

Ruma Murkejee, PhD

Postdoctoral Fellow

1996-2001

Associate Scientist, TUSM

Joaquim Carbó, PhD

PhD student

Univ. of Barcelona

2001-2002

Postdoctoral Fellow, Anton Berns Lab Netherlands
Thomas Young, PhD Postdoctoral Fellow 2001 Research fellow
National University of Singapore
Elena Sotillo, PhD Postdoctoral Fellow 2002-2008 Scientist, CHOPs

 

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PUBMED PUBLICATIONS :


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

25483052. Kurimchak A, Graña X, PP2A: more than a reset switch to activate pRB proteins during the cell cycle and in response to signaling cues. Cell Cycle :(0)2014 Nov 18

23775125. Kurimchak A, Haines DS, Garriga J, Wu S, De Luca F, Sweredoski MJ, Deshaies RJ, Hess S, Graña X, Activation of p107 by fibroblast growth factor, which is essential for chondrocyte cell cycle exit, is mediated by the protein phosphatase 2A/B55a holoenzyme. Mol Cell Biol 33:16(3330-42)2013 Aug

23634261. Kurimchak A, Graña X, PP2A Counterbalances Phosphorylation of pRB and Mitotic Proteins by Multiple CDKs: Potential Implications for PP2A Disruption in Cancer. Genes Cancer 3:11-12(739-48)2012 Nov

22458775. Keskin H, Garriga J, Georlette D, Graña X, Complex effects of flavopiridol on the expression of primary response genes. Cell Div 7:(11)2012 Mar 29

20663872. Jayadeva G, Kurimchak A, Garriga J, Sotillo E, Davis AJ, Haines DS, Mumby M, Graña X, B55alpha PP2A holoenzymes modulate the phosphorylation status of the retinoblastoma-related protein p107 and its activation. J Biol Chem 285:39(29863-73)2010 Sep 24

20634902. Reddy HK, Graña X, Dhanasekaran DN, Litvin J, Reddy EP, Requirement of Cdk4 for v-Ha-ras-Induced Breast Tumorigenesis and Activation of the v-ras-Induced Senescence Program by the R24C Mutation. Genes Cancer 1:1(69-80)2010 Jan

19321444. Sotillo E, Garriga J, Padgaonkar A, Kurimchak A, Cook JG, Graña X, Coordinated activation of the origin licensing factor CDC6 and CDK2 in resting human fibroblasts expressing SV40 small T antigen and cyclin E. J Biol Chem 284:21(14126-35)2009 May 22

18497566. Graña X, Downregulation of the phosphatase nuclear targeting subunit (PNUTS) triggers pRB dephosphorylation and apoptosis in pRB positive tumor cell lines. Cancer Biol Ther 7:6(842-4)2008 Jun

18276582. Sotillo E, Garriga J, Kurimchak A, Graña X, Cyclin E and SV40 small T antigen cooperate to bypass quiescence and contribute to transformation by activating CDK2 in human fibroblasts. J Biol Chem 283:17(11280-92)2008 Apr 25

17949927. Salerno D, Hasham MG, Marshall R, Garriga J, Tsygankov AY, Graña X, Direct inhibition of CDK9 blocks HIV-1 replication without preventing T-cell activation in primary human peripheral blood lymphocytes. Gene 405:1-2(65-78)2007 Dec 15

17483323. Carbone CJ, Graña X, Reddy EP, Haines DS, p21 loss cooperates with INK4 inactivation facilitating immortalization and Bcl-2-mediated anchorage-independent growth of oncogene-transduced primary mouse fibroblasts. Cancer Res 67:9(4130-7)2007 May 1

16720337. Marshall RM, Grana X, Mechanisms controlling CDK9 activity. Front Biosci 11:(2598-613)2006 Sep 1

16288002. Reddy HK, Mettus RV, Rane SG, Graña X, Litvin J, Reddy EP, Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res 65:22(10174-8)2005 Nov 15

16272292. Marshall RM, Salerno D, Garriga J, Graña X, Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human peripheral blood lymphocytes. J Immunol 175:10(6402-11)2005 Nov 15

15467457. Garriga J, Jayaraman AL, Limón A, Jayadeva G, Sotillo E, Truongcao M, Patsialou A, Wadzinski BE, Graña X, A dynamic equilibrium between CDKs and PP2A modulates phosphorylation of pRB, p107 and p130. Cell Cycle 3:10(1320-30)2004 Oct

15276198. Garriga J, Graña X, Cellular control of gene expression by T-type cyclin/CDK9 complexes. Gene 337:(15-23)2004 Aug 4

12861003. Garriga J, Bhattacharya S, Calbó J, Marshall RM, Truongcao M, Haines DS, Graña X, CDK9 is constitutively expressed throughout the cell cycle, and its steady-state expression is independent of SKP2. Mol Cell Biol 23:15(5165-73)2003 Aug

12717421. Bhattacharya S, Garriga J, Calbó J, Yong T, Haines DS, Graña X, SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Oncogene 22:16(2443-51)2003 Apr 24

12401786. Calbó J, Parreño M, Sotillo E, Yong T, Mazo A, Garriga J, Grana X, G1 cyclin/cyclin-dependent kinase-coordinated phosphorylation of endogenous pocket proteins differentially regulates their interactions with E2F4 and E2F1 and gene expression. J Biol Chem 277:52(50263-74)2002 Dec 27

12351382. Rane SG, Mangan JK, Amanullah A, Wong BC, Vora RK, Liebermann DA, Hoffman B, Graña X, Reddy EP, Activation of the Jak3 pathway is associated with granulocytic differentiation of myeloid precursor cells. Blood 100:8(2753-62)2002 Oct 15

11521191. Parreño M, Garriga J, Limón A, Albrecht JH, Graña X, E1A modulates phosphorylation of p130 and p107 by differentially regulating the activity of G1/S cyclin/CDK complexes. Oncogene 20:35(4793-806)2001 Aug 9

10708433. Parreño M, Garriga J, Limón A, Mayol X, Beck GR Jr, Moran E, Graña X, E1A blocks hyperphosphorylation of p130 and p107 without affecting the phosphorylation status of the retinoblastoma protein. J Virol 74:7(3166-76)2000 Apr

9916999. Graña X, Garriga J, Mayol X, Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth. Oncogene 17:25(3365-83)1998 Dec 24

9872325. Garriga J, Peng J, Parreño M, Price DH, Henderson EE, Graña X, Upregulation of cyclin T1/CDK9 complexes during T cell activation. Oncogene 17:24(3093-102)1998 Dec 17

9677324. Garriga J, Limón A, Mayol X, Rane SG, Albrecht JH, Reddy EP, Andrés V, Graña X, Differential regulation of the retinoblastoma family of proteins during cell proliferation and differentiation. Biochem J 333 ( Pt 3):(645-54)1998 Aug 1

9405335. Mayol X, Grana X, The p130 pocket protein: keeping order at cell cycle exit/re-entrance transitions. Front Biosci 3:(d11-24)1998 Jan 1

9580269. Mayol X, Graña X, pRB, p107 and p130 as transcriptional regulators: role in cell growth and differentiation. Prog Cell Cycle Res 3:(157-69)1997

9003389. Garriga J, Segura E, Mayol X, Grubmeyer C, Graña X, Phosphorylation site specificity of the CDC2-related kinase PITALRE. Biochem J 320 ( Pt 3):(983-9)1996 Dec 15

8870681. Garriga J, Mayol X, Graña X, The CDC2-related kinase PITALRE is the catalytic subunit of active multimeric protein complexes. Biochem J 319 ( Pt 1):(293-8)1996 Oct 1

8710362. Mayol X, Garriga J, Graña X, G1 cyclin/CDK-independent phosphorylation and accumulation of p130 during the transition from G1 to G0 lead to its association with E2F-4. Oncogene 13:2(237-46)1996 Jul 18

7651744. Mayol X, Garriga J, Graña X, Cell cycle-dependent phosphorylation of the retinoblastoma-related protein p130. Oncogene 11:4(801-8)1995 Aug 17

7624138. Graña X, Reddy EP, Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene 11:2(211-9)1995 Jul 20

7742528. Guillouf C, Graña X, Selvakumaran M, De Luca A, Giordano A, Hoffman B, Liebermann DA, Dissection of the genetic programs of p53-mediated G1 growth arrest and apoptosis: blocking p53-induced apoptosis unmasks G1 arrest. Blood 85:10(2691-8)1995 May 15

8208557. Graña X, Claudio PP, De Luca A, Sang N, Giordano A, PISSLRE, a human novel CDC2-related protein kinase. Oncogene 9:7(2097-103)1994 Jul

8170997. Graña X, De Luca A, Sang N, Fu Y, Claudio PP, Rosenblatt J, Morgan DO, Giordano A, PITALRE, a nuclear CDC2-related protein kinase that phosphorylates the retinoblastoma protein in vitro. Proc Natl Acad Sci U S A 91:9(3834-8)1994 Apr 26

8361765. Mayol X, Graña X, Baldi A, Sang N, Hu Q, Giordano A, Cloning of a new member of the retinoblastoma gene family (pRb2) which binds to the E1A transforming domain. Oncogene 8:9(2561-6)1993 Sep

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FUNDING HISTORY:

 

Previous Support as Principal Investigator or project leader

  • NIH R29 First Award (R29 GM54894-05) "Regulation of p130 during the cell cycle and Quiescence." 1996-2002
  • Individual allocation from American Cancer Society (#IRG-204) for the project entitled "Regulation of p130 during the cell cycle and Quiescence." 1996
  • Wendy Will Case Grant: "Regulation of p130 during the cell cycle and Quiescence." 1996-1997
  • W.W. Smith Charitable Trust #A9802 “Involvement of T-type cyclin/CDK9 holoenzymes in HIV replication” 1998-1999
  • W.W. Smith Charitable Trust #A9901/ A0002 “HIV replication in macrophages: Role of T-type cyclins” 1999-2002
  • NIH K02 (AI01823) "T-type cyclin/CDK9 complexes in T cell activation, myeloid differentiation and HIV replication" 2000-2006
  • NIH R0-1 AI45450-04 "Role of T-type cyclins in T cell activation and HIV replication."
    TDC 1999-2005
  • Onconova Therapeutics Pharmacologic inhibitors of CDK9 2006-2007
  • NIH P01 (CA095569-02)"G1 cell cycle in Tumorigenesis and Senescence", leader for project #2 "Regulation of p130 by CDKs at the G1/S transition." 2003-2008
  • NIH STTR (1R41MH082775-01) “Identification of Small Pharmacologic Inhibitors of HIV-1 Replication” 2007-2009
  • Pennsylvania Department of Health “Control of cellular and HIV-1 gene expression by cellular CDK9, a potential target for HIV therapeutics” 2009-2010
  • NIH R21 (1R21MH83585-01A2) “Role of Tat and human CDK9 on gene expression alterations coupled to HIV-associated dementia” 2009-2011

 

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