Julia Yaglom, Ph. D., Research Assistant Professor, Dept. of Biochemistry, Boston University School of Medicine

Boston, MA

Current Site Of Practice: Boston University
Hospital Affiliation: Boston Medical Center
Focus of Research:
Fellowship Year: 2008 – 2009
Attended: Boston University

Contact Julia Yaglom


Hsp72 regulates DNA damage signaling in cancer cells

Co-Authors Vladimir Gabai; Michael Sherman

The Biology of Molecular Chaperones

23-28 May, Dubrovnik, Croatia (EMBO meeting)
23 -28 May, 2009 | Dubrovnik, Croatia



Knockout of Hsp72 was demonstrated to promote chromosomal instability and increase radiation sensitivity of mouse fibroblasts. Here we report that downregulation of Hsp72 leads to suppression of a specific branch of the DNA damage response that facilitates DNA repair following genotoxic insults, i.e. reduced accumulation of the phosphorylated form of histone H2AX (gH2AX). This inhibition was due to decreased expression of H2AX as well as higher rate of gH2AX dephosphorylation. Formation of gH2AX and MDC1 radiation-induced foci was partially impaired in Hsp72-depleted cells, which in turn enhanced DNA damage, resulting in sensitization of cells to gIR and doxorubicin. These effects of Hsp72 depletion were dependent on activation of the p53/p21 signaling pathway. Overall, permanent activation of the p53/p21 signaling in Hsp72-depleted cells specifically impaired the gH2AX pathway of the DNA damage response, enhanced DNA damage following genotoxic insults, and led to further stimulation of the p53/p21 pathway, thus creating a positive feedback loop. The resulting strong induction of p21 precipitated senescence following exposure to DNA damaging agents, thus accounting for greater sensitivity to genotoxic stresses. 


M23 -28 May, 2009 | Dubrovnik, Croatia
-28 May, 2009 | Dubrovnik, Croatia


Co-Authors Gabai VL*, Waldman T, Sherman MY.

The heat shock protein Hsp72 is expressed at the elevated levels in various human tumors, and its levels often correlate with poor prognosis. Previously we reported that knockdown of Hsp72 in certain cancer cells but not in untransformed breast epithelial cells triggers senescence via p53-dependent and p53-independent mechanisms. Here we demonstrate that the p53-dependent pathway controlled by Hsp72 depends on the oncogenic form of PI3K. Indeed, upon expression of the oncogenic PI3K, epithelial cells began responding to Hsp72 depletion by activating the p53 pathway. Moreover, in cancer cell lines, activation of the p53 pathway caused by depletion of Hsp72 was dependent on oncogenes that activate the PI3K pathway. On the other hand, the p53-independent senescence pathway controlled by Hsp72 was associated with Ras oncogene. In this pathway, ERKs were critical for senescence, and Hsp72 controlled the ERK-activating kinase cascade at the level of Raf-1. Importantly, upon Ras expression, untransformed cells started responding to knockdown of Hsp72 by constitutive activation of ERKs, culminating in senescence. Therefore, Hsp72 is intimately involved in suppression of at least two separate senescence signaling pathways that are regulated by distinct oncogenes in transformed cells, which explains why cancer cells become "addicted" to this heat shock protein.

Mol Cell Biol. 2008 Nov 10. [Epub ahead of print]

Triggering senescence programs suppresses Chk1 kinase and sensitizes cells to genotoxic stresses

Co-Authors Vladimir L. Gabai, Cornelia O'Callaghan-Sunol, Le Meng, Michael Y. Sherman

Cancer Res. 2008 Mar 15;68(6):1834-42

Depletion of the major heat shock protein Hsp72 leads to activation of the senescence program in a variety of tumor cell lines via both p53-dependent and p53-independent pathways. Here, we found that the Hsp72-depleted cells show defect in phosphorylation and activation of the protein kinase Chk1 by genotoxic stresses, such as UVC irradiation or camptothecin. Under these conditions, phosphorylation of Rad17 was also suppressed, whereas phosphorylation of p53 at Ser(15) was not affected, indicating a specific defect in phosphorylation of a subset of the ATR kinase substrates. Similarly, suppression of Chk1 activation was seen when senescence signaling was triggered by direct stimulation of p53, depletion of Cdc2, or overexpression of the cell cycle inhibitors p21 or p16. Thus, defect in Chk1 activation was not a consequence of the chaperone imbalance, but rather a downstream effect of activation of the senescence signaling. Inhibition of Chk1 was associated with inefficient inter-S phase checkpoint, as Hsp72 depleted cells failed to halt cell cycle progression upon UVC irradiation. Accordingly, sensitivity of cells to genotoxic stimuli after Hsp72 depletion was significantly enhanced. Thus, activation of the senescence signaling causes a defect in the DNA damage response manifested in increased sensitivity to genotoxic stresses.

More: PMID: 18339864