Walker, Cheryl L.

Walker, Cheryl L. Ph.D.

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Research Interests

Cell signaling pathways, endocrine disruptors, cellular responses to oxidative stress and DNA damage, genitourinary and female reproductive tract cancers, polycystic kidney disease (PKD), Tuberous Sclerosis Complex 2 (TSC2) tumor suppressor gene

Current Research

The current focus of my research program is to identify mechanisms responsible for the development of cancers of the male genitourinary tract (kidney and prostate) and female reproductive tract with the goal of utilizing this information to develop new targeted therapies for these diseases. This research is focused on:

1) Alterations in cell signaling pathways that impact TSC2 function such as the mitogenic PI3K signaling pathway and the energy sensing LKB1/AMPK pathway

2) Elucidating how TSC2 and PKD1 interact to regulate key cellular functions

3) Understanding how endocrine disruptors in our environment contribute to the development of hormone-responsive tumors

4) Development of new animal models for studying tumor etiology and efficacy of targeted therapy for cancers of the male genitourinary tract and female reproductive tract

Alterations in cell signaling pathways that impact TSC2 function

TSC2 functions as the gatekeeper for mTOR signaling, a master regulator of protein synthesis and cell growth. We have found that the activity of TSC2 is regulated by AKT phosphorylation, causing TSC2 to partition out of the membrane into the cytosol, separating it from its activation partner TSC1 and its target Rheb. While it is known that TSC2 is activated by AMPK, we have also found that in the absence TSC2, AMPK becomes constitutively active. As a consequence of AMPK activation, the cell cycle regulator p27 becomes sequestered in the cytoplasm, repressing p27’s ability to inhibit its target, CDK2.

Elucidating how TSC2 and PKD1 interact to regulate key cellular functions

Polycystic kidney disease is the most common, potentially lethal genetic alteration in humans. The TSC2 and PKD1 genes lie adjacent to each other on chromosome 16 and are transcribed in a tail-to-tail orientation. We were the first to demonstrate that the protein products of these genes, tuberin and polycystin, are functionally related. Recently, we have found that PKD1 can modulate mTOR repression by TSC2, and studies are underway to determine the nature of this interaction and how it is regulated by cell signaling proteins including c-Src

Understanding how endocrine disruptors in our environment contribute to the development of hormone-responsive tumors

We have recently identified developmental programming as a novel type of gene-environment interaction that determines cancer risk in genetically-susceptible individuals. We found that a brief exposure to a xenoestrogen early in life while a tissue is undergoing development can reprogram gene expression in such as way as to drive tumor development in that tissue later in adult life. For the hormone-responsive tumor uterine leiomyoma, we found this reprogramming caused estrogen-responsive genes to become hyper-sensitive to estrogen, promoting tumor growth in individuals with a genetic susceptibility to these tumors. Studies currently underway have implicated epigenetic alterations, specifically alterations in patterns of histone methylation, as a possible mechanism by which xenoestrogens change the “methyl marks” on chromatin to induce developmental reprogramming.

Development of new animal models for translational research

• The Eker rat model for kidney (renal cell carcinoma) and uterine (leiomyoma and endometrial carcinoma) cancer. Eker rats carry a germline defect in one allele of the Tsc2 gene, and tumors develop in the kidney and uterus of these animals following loss of the wild-type allele. These animals are currently being used in preclinical studies to determine the efficacy of novel mTOR inhibitors, selective estrogen and progesterone receptor modulators (SERMs and SPRMs) and drugs that reverse the effects of loss of Tsc2 function, such CDK2 inhibitors and metformin.

• PTEN knockout mice that develop invasive prostate carcinoma when the PTEN defect is placed on a C57Bl/6 genetic background. These animals are being utilized in chemoprevention studies focusing on finasteride in conjunction with the finasteride clinical trial being conducted at MD Anderson.

• A new LKB1 mouse model for endometrial cancer. We have recently found that LKB1 defects occur with a high frequency in human endometrial carcinoma. To test the hypothesis that loss of LKB1 contributes to the development of endometrial carcinoma, we are generating conditional LKB1 knockout mice with targeted inactivation of LKB1 in the uterus.

Selected Publications

  1. Laping NJ, Everitt JI, Frazier KS, Burgert M, Portis MJ, Cadacio C, Gold LI, Walker CL. Tumor-Specific Efficacy of Transforming Growth Factor-{beta}RI Inhibition in Eker Rats, Clin Cancer Res, 13 (10), 3087-99, 2007
  2. Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis, Nat Cell Biol, 9 (2), 218-24, 2007
  3. Cai SL, Tee AR, Short JD, Bergeron JM, Kim J, Shen J, Guo R, Johnson CL, Kiguchi K, Walker CL. Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning, J Cell Biol, 173 (2), 279-89, 2006
  4. Cook JD, Davis BJ, Cai SL, Barrett JC, Conti CJ, Walker CL. Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance, Proc Natl Acad Sci U S A, 102 (24), 8644-9, 2005
  5. Walker CL, Stewart EA. Uterine fibroids: the elephant in the room, Science, 308 (5728), 1589-92, 2005
  6. Cai S, Everitt JI, Kugo H, Cook J, Kleymenova E, Walker CL. Polycystic kidney disease as a result of loss of the tuberous sclerosis 2 tumor suppressor gene during development, Am J Pathol, 162 (2), 457-68, 2003
  7. Kleymenova EV, Ibraghimov-Beskrovnaya O, Kugoh H, Everitt JI, Xu H, Kiguchi K, Landes G, Harris P, Walker CL. Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene, Mol Cell, 7 (4), 823-32, 2001

Contact Information


Mailing Address: P.O. Box 389, Smithville, Texas 78957
Physical Address: 1808 Park Road 1C, Smithville, Texas 78957
Phone: (512) 237-9525