Section: Research

Heidi Tissenbaum, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Program in Gene Function and Expression
   Program in Molecular Medicine

Other Affiliation(s):
   Interdisciplinary Graduate Program

Identifying Molecular Mechanisms of Aging

Our lab focuses on determining molecular mechanisms of aging using C. elegans. We also work on understanding the connections between fat storage and life span; primarily focused on the insulin/IGF-1 signaling pathway.

CURRENT PROJECTS

LIFE SPAN REGULATION BY JNK KINASE
(Seung Wook Oh and Arnab Mukhopadhyay)

One of the focuses in the lab has been to determine how kinases regulate life span. We identified that c-Jun N-terminal kinase (JNK) is a positive regulator of DAF-16/FOXO for both life span and stress resistance. Our genetic analysis suggests that the JNK pathway acts in parallel with the insulin-like signaling pathway to regulate life span and both pathways converge onto DAF-16/FOXO. We also show that JNK-1 directly interacts with and phosphorylates DAF-16. Moreover, in response to heat stress, JNK-1 promotes the translocation of DAF-16 into the nucleus. Our findings define an interaction between two well conserved proteins, JNK-1 and DAF-16, and provide a mechanism by which JNK regulates longevity and stress resistance. Recent work by several labs has shown that this process is conserved in both flies (Bohrmann/Jasper labs) and mammals (Burgering lab). Our work was recently published in PNAS (March 2005) and discussed on SAGE KE and Cell Metabolism.

Our current model of how JNK-1 promotes the translocation of DAF-16 into the nucleus in response to heat stress. The JNK signaling pathway presumably serves as a molecular sensor for various stresses. Upon detecting environmental cues, JNK-1 transmits the signal by phosphorylating and modulating the nuclear translocation of DAF-16. Once DAF-16 enters the nucleus, it enhances the expression of numerous target genes to prevent damage from any harmful stresses. This would then confer increased stress resistance and help to maintain normal life in C. elegans.

DEFINING MOLECULAR CONNECTIONS BETWEEN LIFE SPAN, FAT STORAGE AND INSULIN/IGF-1 SIGNALING
(Arnab Mukhopadhyay and Srivatsan Padmanabhan)

The prevalence of Type II diabetes is rapidly increasing in the US. This is in part due to the huge increase in the number of obese people. A second factor that predisposes individuals to Type II diabetes is age. As individuals age, they become more likely to develop Type II diabetes. Although the connection between obesity, aging, and the onset of Type II diabetes is clear, the molecular details remain to be determined. The long-term goal of this are of study is to uncover the molecular mechanism that explains the connection between insulin-like signaling, aging and fat storage, so that Type II diabetes and can be better controlled in humans. C. elegans is our model system since the insulin signaling pathway is highly conserved between humans and C. elegans, and nematodes have emerged as an excellent system to study insulin signaling. These studies seek to identify new genes and new pathways coupled to the C. elegans insulin-like signaling pathway to determine how this signaling network controls both life span and fat storage.

Our analysis on this project has focused most recently on the tub-1 gene in C. elegans. In C. elegans, similar to in mammals, mutations in the tubby homolog, tub-1, promote increased fat deposition. We find that mutation in tub-1 also leads to life span extension dependent on daf-16/FOXO. Interestingly, function of tub-1 in fat storage is independent of daf-16. In collaboration with the laboratory of Dr. Marian Walhout (also at UMass) and Dr. Bart dePlancke, a post-doctoral fellow in her lab, we performed a yeast two-hybrid screen and identified a novel TUB-1 interaction partner (RBG-3); a RabGTPase-activating protein. By GFP analysis, we find that both TUB-1 and RBG-3 localize to overlapping neurons. Importantly, RNAi of rbg-3 decreases fat deposition in tub-1 mutants but does not affect life span. We demonstrate that TUB-1 is expressed in ciliated neurons and undergoes both dendritic and ciliary transport. Additionally, tub-1 mutants are chemotaxis defective. Thus, tub-1 may regulate fat storage either by modulating transport, sensing, or responding to signals in ciliated neurons. Taken together, we define a role for tub-1 in regulation of life span and show that tub-1 regulates life span and fat storage by two independent mechanisms. These findings have been published in Cell Metabolism and featured on SAGE KE.

Our data suggests two possible models for TUB-1 regulation of life span and fat storage by independent pathways. (a) For life span regulation, TUB-1 couples to the insulin-like receptor (daf-2) and depends on daf-16. For regulation of metabolism and fat storage, TUB-1 interacts with rbg-3, a RabGAP and possibly controls neuronal transport. (b) Cell non-autonomous regulation of fat and life span by TUB-1.

SIR-2.1 LIFE SPAN REGULATION
(Yamei Wang)

Previously, we have shown that the C. elegans SIR2 homologue, sir-2.1 can extend life span in worms when increased in copy number. Remarkably, the yeast SIR2 gene can also extend life span of the budding yeast, S. cerevisiae (Kaeberlein et al. 1999). The finding that SIR2 can regulate both aging in the worm and replicative aging in yeast mother cells is truly surprising and may also reveal a general molecular mechanism of aging. Currently, we are using genetic and molecular analysis to understand how sir-2.1 can control life span and also identify more players that control life span dependent on sir-2.1. We believe that the results from these studies will be important in understanding the molecular mechanisms of aging and also may reveal universal components to this process.

RECQ HELICASES, GENOMIC STABILITY AND LIFE SPAN
(Melissa M. Grabowski)

Bloom and Werner syndrome are heritable syndromes caused by mutations in the RecQ helicases BLM and WRN respectively. While humans have 5 RecQ helicases (three of which are responsible for disease phenotypes characterized by genomic instability), C. elegans has 4 RecQ helicase family members. To investigate the relationship between genomic stability and organismal life span, we are studying the RecQ helicase family in C. elegans. The four members of the C. elegans RecQ family are T04A11.6 (him-6), F18C5.3 (wrn-1), E03A3.2 (rcq-5), and K02F3.1. HIM-6 is homologous to human BLM, and WRN-1 is homolgous to human WRN. The remaining two helicases RCQ-5 and K02F3.1 are homologous to human RecQL and RecQL5 respectively. We have obtained knock out strains of all four C. elegans RecQ helicases (him-6, wrn-1, rcq-5, K02F3.1) from the CGC. We are currently characterizing the phenotypes of the deletion strains. These studies should provide further insight into the role of genomic instability and aging.

Office: 621
Phone: 508-856-5840
E-mail: Heidi.Tissenbaum@umassmed.edu
Keywords: Organisms - C. elegans, Cancer Biology, Diabetes, Aging, Genetics

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