Proteins of the Homeodomain-Interacting Protein Kinase (HIPK) family regulate an array of processes in mammalian systems, such as the DNA damage response, cellular proliferation and apoptosis. The nematode Caenorhabditis elegans has a single HIPK homologue called HPK-1. Previous studies have implicated HPK-1 in longevity control and suggested that this protein may be regulated in a stress-dependent manner. Here we set out to expand these observations by investigating the role of HPK-1 in longevity and in the response to heat and oxidative stress. We find that levels of HPK-1 are regulated by heat stress, and that HPK-1 contributes to survival following heat or oxidative stress. Additionally, we show that HPK-1 is required for normal longevity, with loss of HPK-1 function leading to a faster decline of physiological processes that reflect premature ageing. Through microarray analysis, we have found that HPK-1-regulated genes include those encoding proteins that serve important functions in stress responses such as Phase I and Phase II detoxification enzymes. Consistent with a role in longevity assurance, HPK-1 also regulates the expression of age-regulated genes. Lastly, we show that HPK-1 functions in the same pathway as DAF-16 to regulate longevity and reveal a new role for HPK-1 in development.

*Background: Tightly regulated pathways maintain the balance between proliferation and differentiation within stem cell populations. In Caenorhabditis elegans, the germline is the only tissue that is maintained by stem-like cells into adulthood. In the current study, we investigated the role played by a member of the Homeodomain interacting protein kinase (HIPK) family of serine/threonine kinases, HPK-1, in the development and maintenance of the C. elegans germline. Results: We report that HPK-1 is required for promotion of germline proliferation during development and into adulthood. Additionally, we show that HPK-1 is required in the soma for regulation of germline proliferation. We also show that HPK-1 is a predominantly nuclear protein expressed in several somatic tissues including germline-interacting somatic cells. Conclusions: Our observations are consistent with a conserved role for HIPKs in the control of cellular proliferation and identify a new context for such control in germ cell proliferation. Developmental