Wikianswers.com says the most common thought about the origin of this expression is the cartoon character Bugs Bunny who frequently inquired “What’s up, Doc?” A reference to ‘whatsup’ was in a short story The Adventures of Shamrock Jolnes and Sixes and Sevens published in 1911 by the famous O’Henry. The character Shamrock Jolnes says, “Good morning, Whatsup.”  Jack London’s The Sea Wolf written in 1904 has a character inquiring of Wolf Larson, “What’s up?” Bugs Bunny appeared in 1940, and probably is responsible for making the phrase popular.